Enzymes

Authors

  • S P H Alexander,

  • A Mathie,

  • J A Peters


Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Adenosine metabolising enzymes

Overview: Adenosine is a multifunctional, ubiquitous molecule that acts at cell-surface 7TM receptors, as well as numerous enzymes, including protein kinases and adenylyl cyclase. Extracellular adenosine accumulates either by export or metabolism, predominantly through ecto-5′-nucleotidase activity (also producing inorganic phosphate). It is inactivated either by extracellular metabolism via adenosine deaminase (producing ammonia as a second product) or, following uptake by nucleoside transporters, via adenosine deaminase or adenosine kinase (requiring ATP as co-substrate). Intracellular metabolism may be enacted by cytosolic 5′-nucleotidases or through S-adenosylhomocysteine hydrolase (producing homocysteine as a second product).

NomenclatureAdenosine deaminaseAdenosine kinaseEcto-5′-NucleotidaseS-Adenosylhomocysteine hydrolase
E.C.3.5.4.42.7.1.203.1.3.53.3.1.1
Preferred abbreviationADAADKNT5ESAHH
Other namesAdenosine aminohydrolaseCD73, 5′-NTAdenosylhomocysteinase
Ensembl IDENSG00000196839ENSG00000156110ENSG00000135318ENSG00000101444
Rank order of affinity2′-Deoxyadenosine > adenosineAdenosine5′-AMP, 5′-GMP, 5′-IMP, 5′-UMP>5′-dAMP, 5′-dGMPS-Adenosylhomocysteine
Products2′-Deoxyinosine, inosine5′-AMPAdenosine, guanine, inosine, uridineAdenosine
Selective inhibitorsEHNA, 20′-deoxycoformycinA134974 (pIC50 10.2, McGaraughty et al., 2001), ABT702 (pIC50 8.8, Jarvis et al., 2000)αβ-methyleneADP

Other forms of adenosine deaminase act on ribonucleic acids and may be divided into two families: ADAT1 (ENSG00000065457) deaminates transfer RNA; ADAR (ENSG00000160710, EC 3.5.4.—, also known as 136 kDa double-stranded RNA-binding protein, P136, K88DSRBP, interferon-inducible protein 4); ADARB1 (ENSG00000197381, EC 3.5.-.-, also known as dsRNA adenosine deaminase) and ADARB2 (ENSG00000185736, EC 3.5.-.-, also known as dsRNA adenosine deaminase B2, RNA-dependent adenosine deaminase 3) act on double-stranded RNA. Particular polymorphisms of the ADA gene result in loss-of-function and severe combined immunodeficiency syndrome. Adenosine deaminase is able to complex with dipeptidyl peptidase IV (EC 3.4.14.5, also known as T-cell activation antigen CD26, TP103, adenosine deaminase complexing protein 2, ENSG00000197635) to form a cell-surface activity (Kameoka et al., 1993).

Cytosolic 5′-nucleotidase may be divided into IA (ENSG00000116981, NT5C1A), IB (ENSG00000185013, NT5C1B), II (ENSG00000076685, NT5C2), III (ENSG00000122643, NT5C3) and 5′(3′)-nucleotidases (ENSG00000125458, NT5C), together with a mitochondrial isoform (ENSG00000205309, NT5M).

Abbreviations: 5′-AMP, adenosine 5′-monophosphate; 5′NT, 5′-nucleotidase; A134974, N7-[(1′R,2′S,3′R,4′S)-2′,3′-dihydroxy-4′-aminocyclo-pentyl]-4-amino-5-iodopyrrolopyrimidine; ABT702, 4-amino-5-(3-bromophenyl)-7-(6-morpholinopyridin-3-yl)pyrido[2,3-d]pyrimidine; ADA, adenosine deaminase; ADK, adenosine kinase; EHNA, erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride

Further Reading

Blackburn MR, Kellems RE (2005). Adenosine deaminase deficiency: metabolic basis of immune deficiency and pulmonary inflammation. Adv Immunol86: 1–41.

Boison D (2006). Adenosine kinase, epilepsy and stroke: mechanisms and therapies. Trends Pharmacol Sci27: 652–658.

Buckley RH (2004). Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Annu Rev Immunol22: 625–655.

Hershfield MS (2005). New insights into adenosine-receptor-mediated immunosuppression and the role of adenosine in causing the immunodeficiency associated with adenosine deaminase deficiency. Eur J Immunol35: 25–30.

Hunsucker SA, Mitchell BS, Spychala J (2005). The 5′-nucleotidases as regulators of nucleotide and drug metabolism. Pharmacol Ther107: 1–30.

Keegan LP, Leroy A, Sproul D, O'Connell MA (2004). Adenosine deaminases acting on RNA (ADARs): RNA-editing enzymes. Genome Biol5: 209.

Kloor D, Osswald H (2004). S-Adenosylhomocysteine hydrolase as a target for intracellular adenosine action. Trends Pharmacol Sci25: 294–297.

References

Jarvis MF et al. (2000). J Pharmacol Exp Ther295: 1156–1164.

Kameoka J et al. (1993). Science261: 466–469.

McGaraughty S et al. (2001). J Pharmacol Exp Ther296: 501–509.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Adenylyl cyclases (E.C. 4.6.1.1)

Overview: Adenylyl cyclase (ENSF00000000188) converts 5′-ATP to 3′,5′-adenosine monophosphate and pyrophosphate. Mammalian membrane-bound adenylyl cyclases are typically made up of two clusters of six transmembrane domains separating two intracellular, overlapping catalytic domains that are the target for the nonselective activators forskolin, NKH477 (except AC9, Premont et al., 1996) and Gαs (the stimulatory G protein α subunit). Adenosine and its derivatives (e.g. 2′,5′-dideoxyadenosine), acting through the P-site, appears to be a physiological inhibitor of adenylyl cyclase activity (Tesmer et al., 2000). Three families of adenylyl cyclase are distinguishable: Ca2+/CaM-stimulated (AC1, AC3 and AC8), Ca2+-inhibitable (AC5 and AC6) and Ca2+-insensitive (AC2, AC4 and AC7) forms.

NomenclatureAC1AC2AC3AC4AC5
Other namesAC IAC II, HBCA2AC III, olfactory typeAC IVAC V
Ensembl IDENSG00000164742ENSG00000078295ENSG00000138031ENSG00000129467ENSG00000173175
Endogenous activatorsCa2+/CaM (Tang et al., 1991), PKC-evoked phosphorylation (Jacobowitz et al., 1993)Gβγ (Taussig et al., 1993), PKC-evoked phosphorylation (Chen and Iyengar, 1993; Lustig et al., 1993)Ca2+/CaM (Choi et al., 1992), PKC-evoked phosphorylation (Jacobowitz et al., 1993)Gβγ (Gao and Gilman, 1991)PKC-evoked phosphorylation (Kawabe et al., 1994)
Endogenous inhibitorsGαi (Taussig et al., 1994), Gαo (Taussig et al., 1994), Gβγ (Taussig et al., 1993)Gαi (Taussig et al., 1994), RGS2 (Sinnarajah et al., 2001), CaM kinase II-evoked phosphorylation (Wayman et al., 1995)PKC-evoked phosphorylation (Zimmermann and Taussig, 1996)Gαi (Taussig et al., 1994), Ca2+ (Ishikawa et al., 1992), PKA-evoked phosphorylation (Iwami et al., 1995)
Selective inhibitorsNKY80 (Onda et al., 2001)
NomenclatureAC6AC7AC8AC9
Other namesAC VI, Ca2+-inhibitable cyclaseAC VIIAC VIIIAC IX
Ensembl IDENSG00000174233ENSG00000121281ENSG00000155897ENSG00000162104
Endogenous activatorsPKC-evoked phosphorylation (Watson et al., 1994)Ca2+ (Cali et al., 1994)
Endogenous inhibitorsGαi (Taussig et al., 1994), Ca2+ (Yoshimura and Cooper, 1992), PKA-evoked phosphorylation (Chen et al., 1997), PKC-evoked phosphorylation (Lai et al., 1999)Ca2+/calcineurin (Paterson et al., 2000)

Nitric oxide has been proposed to inhibit AC5 and AC6 selectively (Hill et al., 2000), although it is unclear whether this phenomenon is of physiological significance. A soluble adenylyl cyclase has been described (ENSG00000143199, Buck et al., 1999), unaffected by either Gα or Gβγ subunits, which has been suggested to be a cytoplasmic bicarbonate (pH-insensitive) sensor (Chen et al., 2000).

Abbreviations: CaM, calmodulin; NKH477, 6-(3-dimethylaminopropionyl) forskolin hydrochloride; NKY80, 2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone; PKA, protein kinase A or cyclic AMP-dependent protein kinase; PKC, protein kinase C; RGS2, Regulator of G-protein signalling 2 (ENSG00000116741)

Further Reading

Beazely MA, Watts VJ (2006). Regulatory properties of adenylate cyclases type 5 and 6: A progress report. Eur J Pharmacol535: 1–12.

Cooper DMF, Crossthwaite AJ (2006). Higher-order organization and regulation of adenylyl cyclases. Trends Pharmacol Sci27: 426–431.

Feldman RD, Gros R (2007). New insights into the regulation of cAMP synthesis beyond GPCR/G protein activation: implications in cardiovascular regulation. Life Sci81: 267–271.

Kamenetsky M, Middelhaufe S, Bank EM, Levin LR, Buck J, Steegborn C (2006). Molecular details of cAMP generation in mammalian cells: a tale of two systems. J Mol Biol362: 623–639.

Linder JU (2006). Class III adenylyl cyclases: molecular mechanisms of catalysis and regulation. Cell Mol Life Sci63: 1736–1751.

Watts VJ, Neve KA (2005). Sensitization of adenylate cyclase by Gái/o-coupled receptors. Pharmacol Ther106: 405–421.

Willoughby D, Cooper DMF (2007). Organization and Ca2+ regulation of adenylyl cyclases in cAMP microdomains. Physiol Rev87: 965–1010.

References

Buck J et al. (1999). Proc Natl Acad Sci USA96: 79–84.

Cali JJ et al. (1994). J Biol Chem269: 12190–12195.

Chen JQ, Iyengar R (1993). J Biol Chem268: 12253–12256.

Chen Y et al. (1997). Proc Natl Acad Sci USA94: 14100–14104.

Chen Y et al. (2000). Science289: 625–628.

Choi EJ et al. (1992). Biochemistry31: 6492–6498.

Gao BN, Gilman AG (1991). Proc Natl Acad Sci USA88: 10178–10182.

Hill J et al. (2000). Cell Signal12: 233–237.

Ishikawa Y et al. (1992). J Biol Chem267: 13553–13557.

Iwami G et al. (1995). J Biol Chem270: 12481–12484.

Jacobowitz O et al. (1993). J Biol Chem268: 3829–3832.

Kawabe J-I et al. (1994). J Biol Chem269: 16554–16558.

Lai H-L et al. (1999). Mol Pharmacol56: 644–650.

Lustig KD et al. (1993). J Biol Chem268: 13900–13905.

Paterson JM et al. (2000). J Neurochem75: 1358–1367.

Premont RT et al. (1996). J Biol Chem271: 13900–13907.

Sinnarajah S et al. (2001). Nature409: 1051–1055.

Taussig R et al. (1993). J Biol Chem268: 9–12.

Taussig R et al. (1994). J Biol Chem269: 6093–6100.

Tesmer JJ et al. (2000). Biochemistry39: 14464–14471.

Watson PA et al. (1994). J Biol Chem269: 28893–28898.

Wayman GA et al. (1995). J Biol Chem270: 21480–21486.

Yoshimura M, Cooper DM (1992). Proc Natl Acad Sci USA89: 6716–6720.

Zimmermann G, Taussig R (1996). J Biol Chem271: 27161–27166.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Amino acid hydroxylases (E.C.1.14.16.-)

Overview: The amino acid hydroxylases (monooxygenases) are iron-containing enzymes which utilise molecular oxygen and tetrahydrobiopterin as co-substrate and co-factor, respectively.

NomenclatureL-Phenylalanine hydroxylaseL-Tryptophan hydroxylaseL-Tyrosine hydroxylase
E.C.1.14.16.11.14.16.41.14.16.2
Preferred abbreviationPHTPHTH
Other namesPhenylalanine 4-monooxygenaseTryptophan 5-monooxygenaseTyrosine 3-monooxygenase
Ensembl IDENSG00000171759TPH1 ENSG00000129167; TPH2 ENSG00000139287ENSG00000180176
ProductTyrosine5-HydroxytryptophanDOPA
Selective inhibitorsα-Methylphenylalanine (Greengard et al., 1976), PCPAFenfluramine, PCPA, α-propyldopacetamide, 6-fluorotryptophan (Nicholson and Wright, 1981)3-Chlorotyrosine, 3-iodotyrosine, α-methyltyrosine, α-propyldopacetamide

Abbreviations: DOPA, 3, 4-dihydroxyphenylalanine; PCPA, 4-chlorophenylalanine

Further Reading

Dunkley PR, Bobrovskaya L, Graham ME, von Nagy-Felsobuki EI, Dickson PW (2004). Tyrosine hydroxylase phosphorylation: regulation and consequences. J Neurochem91: 1025–1043.

Fujisawa H, Okuno S (2005). Regulatory mechanism of tyrosine hydroxylase activity. Biochem Biophys Res Commun338: 271–276.

Kobayashi K, Nagatsu T (2005). Molecular genetics of tyrosine 3-monooxygenase and inherited diseases. Biochem Biophys Res Commun338: 267–270.

Lehmann IT, Bobrovskaya L, Gordon SL, Dunkley PR, Dickson PW (2006). Differential regulation of the human tyrosine hydroxylase isoforms via hierarchical phosphorylation. J Biol Chem281: 17644–17651.

Preisig M, Ferrero F, Malafosse A (2005). Monoamine oxidase A and tryptophan hydroxylase gene polymorphisms: are they associated with bipolar disorder? Am J Pharmacogenomics5: 45–52.

Zhang X, Beaulieu JM, Gainetdinov RR, Caron MG (2006). Functional polymorphisms of the brain serotonin synthesizing enzyme tryptophan hydroxylase-2. Cell Mol Life Sci63: 6–11.

References

Greengard O et al. (1976). Science192: 1007–1008.

Nicholson AN, Wright CM (1981). Neuropharmacology20: 335–339.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Cyclooxygenase (E.C. 1.14.99.1)

Overview: Prostaglandin (PG) G/H synthase, most commonly referred to as cyclooxygenase (COX, (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate,hydrogen-donor:oxygen oxidoreductase) activity, catalyses the formation of PGG2 from arachidonic acid. Hydroperoxidase activity inherent in the enzyme catalyses the formation of PGH2 from PGG2. COX-1 and −2 can be nonselectively inhibited by ibuprofen, ketoprofen, naproxen, indometacin and paracetamol (acetaminophen).

NomenclatureCOX-1COX-2
Other namesProstaglandin G2/H2 synthase-1Prostaglandin G2/H2 synthase-2
Ensembl IDENSG00000095303ENSG00000073756
SubstratesArachidonic acidArachidonic acid, docosahexaenoic acid
Selective inhibitorsFR122047 (7.5, Ochi et al., 2000), valeroylsalicylate (Bhattacharyya et al., 1995)Diclofenac (6.7), celecoxib (5.1), rofecoxib (4.3), valdecoxib, parecoxib, etoricoxib, lumiracoxib

Abbreviations: FR122047, 1-([4,5-bis{methoxyphenyl}-2-thazoyl]carbonyl)-4-methyl)piperazine hydrochloride

Further Reading

Blobaum AL, Marnett LJ (2007). Structural and functional basis of cyclooxygenase inhibition. J Med Chem50: 1425–1441.

Burian M, Geisslinger G (2005). COX-dependent mechanisms involved in the antinociceptive action of NSAIDs at central and peripheral sites. Pharmacol Ther107: 139–154.

Cha YI, DuBois RN (2007). NSAIDs and cancer prevention: targets downstream of COX-2. Annu Rev Med58: 239–252.

Dogne JM, Supuran CT, Pratico D (2005). Adverse cardiovascular effects of the coxibs. J Med Chem48: 2251–2257.

Eisinger AL, Prescott SM, Jones DA, Stafforini DM (2007). The role of cyclooxygenase-2 and prostaglandins in colon cancer. Prostaglandins Other Lipid Mediat82: 147–154.

Luan Y, Xu W (2006). The function of the selective inhibitors of cyclooxygenase 2. Mini Rev Med Chem6: 1375–1381.

Maxwell SR, Payne RA, Murray GD, Webb DJ (2006). Selectivity of NSAIDs for COX-2 and cardiovascular outcome. Br J Clin Pharmacol62: 243–245.

Mitchell JA, Warner TD (2006). COX isoforms in the cardiovascular system: understanding the activities of non-steroidal anti-inflammatory drugs. Nat Rev Drug Discov5: 75–86.

Rajakariar R, Yaqoob MM, Gilroy DW (2006). COX-2 in inflammation and resolution. Mol Interv6: 199–207.

Roos KL, Simmons DL (2005). Cyclooxygenase variants: the role of alternative splicing. Biochem Biophys Res Commun338: 62–69.

Rouzer CA, Marnett LJ (2005). Structural and functional differences between cyclooxygenases: fatty acid oxygenases with a critical role in cell signaling. Biochem Biophys Res Commun338: 34–44.

Sarkar FH, Adsule S, Li Y, Padhye S (2007). Back to the future: COX-2 inhibitors for chemoprevention and cancer therapy. Mini Rev Med Chem7: 599–608.

Wu KK (2005). Control of cyclooxygenase-2 transcriptional activation by pro-inflammatory mediators. Prostaglandins Leukot Essent Fatty Acids72: 89–93.

References

Bhattacharyya DK et al. (1995). Arch Biochem Biophys317: 19–24.

Ochi T et al. (2000). Eur J Pharmacol391: 49–54.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Decarboxylases (E.C. 4.1.1.-)

Overview: The decarboxylases generate CO2 and the indicated products from acidic substrates, requiring pyridoxal phosphate (ADC, AADC, GAD, HDC, ODC and PSDC or pyruvate (SAMDC and PSDC) as a co-factor. The activity of ODC is regulated by the presence of an antizyme (ENSF00000002504) and an ODC antizyme inhibitor (ENSF00000002504).

NomenclatureS-Adenosylmethionine decarboxylaseL-Arginine decarboxylaseL-Aromatic amino-acid decarboxylaseGlutamic acid decarboxylase
E.C.4.1.1.504.1.1.194.1.1.284.1.1.15
Preferred abbreviationSAMDCADCAADCGAD
Other namesOrnithine decarboxylase- like protein (Zhu et al., 2004)DOPA decarboxylase (DDC), 5-hydroxytryptophan decarboxylaseGAD1 (GAD65), GAD2 (GAD67)
Ensembl IDENSG00000123505ENSG00000142920ENSG00000132437ENSG00000128683, ENSG00000136750
Substrate(s)S-AdenosylmethionineL-ArginineDOPA, L-tryptophan, 5-hydroxy-L-tryptophanL-Glutamate, L-aspartate
Product(s)5′-Deoxyadenosyl- (3-aminopropyl) methylsulfoniumAgmatine5-Hydroxytryptamine, dopamineGABA
Selective inhibitorsSAM486A (8.0; Stanek et al., 1993), AMABenserazide, carbidopa, 3-hydroxybenzylhydrazine, L-α-methyldopaS-Allylglycine

The presence of a functional ADC activity in human tissues has been questioned (Coleman et al., 2004). s-Allylglycine is also an inhibitor of SAMDC (Pajunen et al., 1979).

NomenclatureHistidine decarboxylaseOrnithine decarboxylasePhosphatidylserine decarboxylase
E.C.4.1.1.224.1.1.174.1.1.65
Preferred abbreviationHDCODCPSDC
Ensembl IDENSG00000140287ENSG00000115758ENSG00000100141
Substrate(s)L-HistidineL-OrnithinePhosphatidylserine
ProductHistaminePutrescinePhosphatidylethanolamine
Selective inhibitorsFMH (Garbarg et al., 1980)DFMO, APA

Abbreviations: AMA, S-(5′-deoxy-5′-adenosyl)-methylthioethyl-hydroxylamine; APA, 1-aminooxy-3-aminopropane; DFMO, α-difluoromethyl-L-ornithine, also known as eflornithine; FMH, α-fluoromethylhistidine; SAM, S-adenosylmethionine; SAM486A, 1-guanidinoimino-2,3-dihydroindene-4-carboximidamide also known as CGP48664

Further Reading

Ai W, Takaishi S, Wang TC, Fleming JV (2006). Regulation of L-histidine decarboxylase and its role in carcinogenesis. Prog Nucleic Acid Res Mol Biol81: 231–270.

Akbarian S, Huang HS (2006). Molecular and cellular mechanisms of altered GAD1/GAD67 expression in schizophrenia and related disorders. Brain Res Rev52: 293–304.

Moya-Garcia AA, Medina MA, Sanchez-Jimenez F (2005). Mammalian histidine decarboxylase: from structure to function. Bioessays27: 57–63.

Pegg AE (2006). Regulation of ornithine decarboxylase. J Biol Chem281: 14529–14532.

Pons R, Ford B, Chiriboga CA, Clayton PT, Hinton V, Hyland K et al. (2004). Aromatic L-amino acid decarboxylase deficiency: clinical features, treatment, and prognosis. Neurology62: 1058–1065.

Smith KJ, Skelton H (2006). α-Difluoromethylornithine, a polyamine inhibitor: its potential role in controlling hair growth and in cancer treatment and chemo-prevention. Int J Dermatol45: 337–344.

Tiwari HK, Bouchard L, Perusse L, Allison DB (2005). Is GAD2 on chromosome 10p12 a potential candidate gene for morbid obesity? Nutr Rev63: 315–319.

Vance JE, Vance DE (2004). Phospholipid biosynthesis in mammalian cells. Biochem Cell Biol82: 113–128.

References

Coleman CS et al. (2004). Biochem J379: 849–855.

Garbarg M et al. (1980). J Neurochem35: 1045–1052.

Pajunen AE et al. (1979). J Neurochem32: 1401–1408.

Stanek J et al. (1993). J Med Chem36: 2168–2171.

Zhu MY et al. (2004). Biochim Biophys Acta1670: 156–164.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Endocannabinoid metabolising enzymes

Overview: the principal endocannabinoids are 2-arachidonoylglycerol (2AG) and anandamide (N-arachidonoylethanolamine, AEA), thought to be generated primarily by diacylglycerol lipase (DAGL) and N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD). Aside from oxidative metabolism by cyclooxygenase and lipoxygenase enzymes, inactivation of these endocannabinoids appears to occur predominantly through monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), respectively.

NomenclatureDiacylglycerol lipase αDiacylglycerol lipase βN-Acylphosphatidylethanolamine-phospholipase D
Preferred abbreviationDAGLαDAGLβNAPE-PLD
E.C.3.1.1._3.1.1._
Other namesNeural stem cell-derived dendrite regulatorKCCR13L
Ensembl IDENSG00000134780ENSG00000164535ENSG00000161048
Selective inhibitors (pIC50)Tetrahydrolipstatin (7.2, Bisogno et al., 2003), RHC80267Tetrahydrolipstatin (7.0, Bisogno et al., 2003), RHC80267

NAPE-PLD activity appears to be enhanced by polyamines in the physiological range (Liu et al., 2002), but fails to transphosphatidylate with alcohols (Petersen and Hansen, 1999) unlike phosphatidylcholine-specific phospholipase D.

NomenclatureMonoacylglycerol lipaseFatty acid amide hydrolase-1Fatty acid amide hydrolase-2N-Acylethanolamine acid amidase
Preferred abbreviationMAGLFAAH1FAAH2NAAA
E.C.3.1.1.233.1._._3.1._._3.5.1._
Other namesHU-K5, lysophospholipase homologOleamide hydrolase, anandamide hydrolaseAcid ceramidase-like protein, N-acylsphingosine amidohydrolase-like, N-palmitoylethanolamine acid amidase
Ensembl IDENSG00000074416ENSG00000117480ENSG00000165591ENSG00000138744
Potency order2OG=2AG>AEA (Ghafouri et al., 2004)AEA>ODA>OEA>PEA> NOT (Wei et al., 2006)ODA>OEA>AEA>PEA (Wei et al., 2006)PEA>MEA>SEA>OEA>AEA (Ueda et al., 2001)
Selective inhibitors (pIC50)URB597 (6.3-7.0, Wei et al., 2006), OL135 (7.4, Wei et al., 2006)URB597 (7.5-8.3, Wei et al., 2006), OL135 (7.9, Wei et al., 2006)CCP (5.3, Tsuboi et al., 2004)

A pharmacologically-distinct MAGL has recently been described in microglial cells (Muccioli et al., 2007). URB602 was initially described as a selective MAGL inhibitor (Hohmann et al., 2005), although a subsequent study suggested it possessed significant inhibitory potency at FAAH1 (Vandevoorde et al., 2007). URB754 also showed initial promise as a selective MAGL inhibitor (Makara et al., 2005), although a corrigendum ascribed MAGL inhibition to a contaminant (Makara et al., 2007).

Abbreviations: 2AG, 2-arachidonoylglycerol; 2OG, 2-oleoylglycerol; AEA, anandamide; CCP, N-cyclohexylcarbonylpentadecylamine; DAGL, diacylglycerol lipase; FAAH, fatty acid amide hydrolase; MAGL, monoacylglycerol lipase; MEA, N-myristoylethanolamine; NAAA, N-acylethanolamine acid amidase; NAPE-PLD, N-acylphosphatidylethanolamine-phospholipase D; NOT, N-oleoyltaurine; ODA, octadec(9,10z) enamide; OEA, N-oleoylethanolamine; OL135, 1-oxo-1-[5-(2-pyridyl)oxazol-2-yl]-7-phenylheptane; PEA, N-palmitoylethanolamine; RHC80267, 1,6-bis(cyclohexyloximinocarbonylamino)hexane; SEA, N-stearoylethanolamine; URB597, cyclohexyl carbamic acid 3′-carbamoyl-biphenyl-3-yl ester; URB602, [1,1′-biphenyl]-3-yl-carbamic acid, cyclohexyl ester; URB754, 6-methyl-2-p-tolylaminobenzo[d]oxazin-4-one

Further Reading

Alexander SPH, Kendall DA (2007). The complications of promiscuity: endocannabinoid action and metabolism. Br J Pharmacol152: 602–623.

Di Marzo V, Bisogno T, De Petrocellis L (2007). Endocannabinoids and Related Compounds: Walking Back and Forth between Plant Natural Products and Animal Physiology. Chem Biol14: 741–756.

Di Marzo V, Petrosino S (2007). Endocannabinoids and the regulation of their levels in health and disease. Curr Opin Lipidol18: 129–140.

Fowler CJ, Holt S, Nilsson O, Jonsson KO, Tiger G, Jacobsson SO (2005). The endocannabinoid signaling system: Pharmacological and therapeutic aspects. Pharmacol Biochem Behav81: 248–262.

McKinney MK, Cravatt BF (2005). Structure and function of fatty acid amide hydrolase. Annu Rev Biochem74: 411–432.

References

Bisogno T et al. (2003). J Cell Biol163: 463–468.

Ghafouri N et al. (2004). Br J Pharmacol143: 774–784.

Hohmann AG et al. (2005). Nature435: 1108–1112.

Liu Q et al. (2002). Chem Phys Lipids115: 77–84.

Makara JK et al. (2005). Nat Neurosci8: 1139–1141.

Makara JK et al. (2007). Nat Neurosci10: 134.

Muccioli GG et al. (2007). J Neurosci27: 2883–2889.

Petersen G, Hansen HS (1999). FEBS Lett455: 41–44.

Tsuboi K et al. (2004). Biochem J379: 99–106.

Ueda N et al. (2001). J Biol Chem276: 35552–35557.

Vandevoorde S et al. (2007). Br J Pharmacol150: 186–191.

Wei BQ et al. (2006). J Biol Chem281: 36569–36578.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Inositol monophosphatase (E.C. 3.1.3.25)

Overview: Inositol monophosphatase (IMPase, myo-inositol-1(or 4)-phosphate phosphohydrolase) is a magnesium-dependent homodimer which hydrolyses myo-inositol monophosphate to generate myo-inositol and phosphate. Glycerol may be a physiological phosphate acceptor. Lithium is a nonselective un-competitive inhibitor of IMPase (pKica. 3.5, McAllister et al., 1992). IMPase activity may be inhibited competitively by L690330 (pKi 5.5, McAllister et al., 1992), although the enzyme selectivity is not yet established.

NomenclatureIMPase 1IMPase 2
Other namesIMPA1IMPA2
Ensembl IDENSG00000133731ENSG00000141401
Rank order of affinityInositol 4-phosphate>inositol 3-phosphate>inositol 1-phosphate (McAllister et al., 1992)

Polymorphisms in either of the genes encoding these enzymes have been linked with bipolar disorder (Sjoholt et al., 1997; Yoshikawa et al., 1997; Sjoholt et al., 2000).

Abbreviation: L690330, 1-(4-hydroxyphenoxy)ethane-1,1-bisphosphonate

Further Reading

Ikeda A, Kato T (2003). Biological predictors of lithium response in bipolar disorder. Psychiatry Clin Neurosci57: 243–250.

Lenox RH, Wang L (2003). Molecular basis of lithium action: integration of lithium-responsive signaling and gene expression networks. Mol Psychiatry8: 135–144.

Miller DJ, Allemann RK (2007). myo-Inositol monophosphatase: a challenging target for mood stabilising drugs. Mini Rev Med Chem7: 107–113.

References

McAllister G et al. (1992). Biochem J284: 749–754.

Sjoholt G et al. (1997). Genomics45: 113–122.

Sjoholt G et al. (2000). Mol Psychiatry5: 172–180.

Yoshikawa T et al. (1997). Mol Psychiatry2: 393–397.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Lipoxygenases (E.C. 1.13.11.-)

Overview: The lipoxygenases (LOXs) are a structurally related family of non-heme iron dioxygenases that function in the production, and in some cases metabolism, of fatty acid hydroperoxides. In humans there are five lipoxygenases, the 5S-(arachidonate : oxygen 5-oxidoreductase), 12R-(arachidonate 12-lipoxygenase, 12R-type), 12S-(arachidonate : oxygen 12-oxidoreductase), and two distinct 15S-(arachidonate : oxygen 15-oxidoreductase) LOXs that oxygenate arachidonic acid in different positions along the carbon chain and form the corresponding 5S-, 12S-, 12R-, or 15S-hydroperoxides, respectively. The sixth lipoxygenase member, epidermal lipoxygenase 3 (E-LOX), metabolises the product from the 12R-lipoxygenase (12R-HPETE) to a specific epoxyalcohol compound (Yu et al., 2003). Some general LOX inhibitors are NDGA and esculetin.

Nomenclature5-LOX12R-LOX12S-LOX
E.C.1.13.11.341.13.11.-1.13.11.31
Other namesALOX5ALOX12BALOX12, platelet-type 12-lipoxygenase
Ensembl IDENSG00000012779ENSG00000179477ENSG0000108839
SubstratesArachidonic acidMethyl arachidonateArachidonic acid
ActivatorsFLAP
Selective inhibitorsZileuton, CJ13610 (Fischer et al., 2004)
Nomenclature15-LOX-115-LOX-2E-LOX
E.C.1.13.11.331.13.11.331.13.11.-
Other namesALOX15, arachidonate W-6 lipoxygenaseALOX15BEpidermis type LOX 3
Ensembl IDENSG00000161905ENSG0000179593ENSG00000179148
SubstratesLinoleic acid, arachidonic acidArachidonic acid12R-HPETE

An 8-LOX (EC 1.13.11.40, arachidonate-oxygen 8-oxidoreductase) may be the mouse orthologue of 15-LOX-2 (Furstenberger et al., 2002). Zileuton and caffeic acid are used as 5-lipoxygenase inhibitors, while baicalein and CDC are 12-lipoxygenase inhibitors. The specificity of these inhibitors has not been rigorously assessed with all LOX forms: baicalein, along with other flavonoids, such as fisetin and luteolin, also inhibits 15-LOX-1 (Sadik et al., 2003).

Abbreviations: CDC, cinnamyl-3,4-dihydroxy-α-cyanocinnamate; CJ13610, 1-carboxamido-1-(3-S-[4-[2-methylimididazole]-thiophenyl])-4-cyclopent ylether; esculetin, 6,7-dihydroxycoumarin; 12R-HPETE, 12R-hydroperoxyeicosatetraenoic acid; FLAP, 5-lipoxygenase-activating protein, also known as MK-886-binding protein (ENSG00000132965); NDGA, nordihydroguaiaretic acid

Further Reading

Funk CD (2006). Lipoxygenase pathways as mediators of early inflammatory events in atherosclerosis. Arterioscler Thromb Vasc Biol26: 1204-1206.

Furstenberger G, Epp N, Eckl KM, Hennies HC, Jorgensen C, Hallenborg P et al. (2007). Role of epidermis-type lipoxygenases for skin barrier function and adipocyte differentiation. Prostaglandins Other Lipid Mediat82: 128–134.

Kuhn H, O'Donnell VB (2006). Inflammation and immune regulation by 12/15-lipoxygenases. Prog Lipid Res45: 334–356.

Murphy RC, Gijón MA (2007). Biosynthesis and metabolism of leukotrienes. Biochem J405: 379–395.

Osher E, Weisinger G, Limor R, Tordjman K, Stern N (2006). The 5 lipoxygenase system in the vasculature: emerging role in health and disease. Mol Cell Endocrinol252: 201–206.

Powell WS, Rokach J (2005). Biochemistry, biology and chemistry of the 5-lipoxygenase product 5-oxo-ETE. Prog Lipid Res44: 154–183.

Radmark O, Samuelsson B (2007). 5-lipoxygenase: regulation and possible involvement in atherosclerosis. Prostaglandins Other Lipid Mediat83: 162–174.

Rubin P, Mollison KW (2007). Pharmacotherapy of diseases mediated by 5-lipoxygenase pathway eicosanoids. Prostaglandins Other Lipid Mediat83: 188–197.

Werz O, Steinhilber D (2006). Therapeutic options for 5-lipoxygenase inhibitors. Pharmacol Ther112: 701–718.

References

Fischer L et al. (2004). Br J Pharmacol142: 861–868.

Furstenberger G et al. (2002). Prostaglandins Other Lipid Mediat68–69: 235–243.

Sadik CD et al. (2003). Biochem Pharmacol65: 773–781.

Yu Z et al. (2003). Proc Natl Acad Sci USA100: 9162–9167.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1-S209.

Nitric oxide synthase (E.C. 1.14.13.39)

Overview: The nomenclature suggested by NC-IUPHAR of NOS I, II and III (see Moncada et al., 1997) has not gained wide acceptance. Nitric oxide synthases (NOS, L-arginine, NADPH2:oxygen oxidoreductase (nitric-oxide-forming)) utilise L-arginine (not D-arginine) and molecular oxygen to generate nitric oxide and L-citrulline. eNOS and nNOS isoforms are activated at concentrations of calcium greater than 100 nM, while iNOS shows higher affinity for Ca2+/calmodulin and thus appears to be constitutively active. All the three isoforms are homodimers and require tetrahydrobiopterin, flavin adenine dinucleotide, flavin mononucleotide and NADPH for catalytic activity. L-NAME is an inhibitor of all three isoforms, with an IC50 value in the micromolar range.

NomenclatureEndothelial NOSInducible NOSNeuronal NOS
Preferred abbreviationeNOSiNOSnNOS
Other namesNOS III, NOS-3, ecNOSNOS II, NOS-2NOS I, NOS-1, brain NOS
Ensembl IDENSG00000164867ENSG00000007171ENSG00000089250
Selective inhibitors1400W (8.2, Garvey et al., 1997), 2-amino-4-methylpyridine (7.4, Faraci et al., 1996), PIBTU (7.3, Garvey et al., 1994), NIL (5.5, Moore et al., 1994), aminoguanidine (Corbett and McDaniel, 1992)3-Bromo-7NI (6.1-6.5, Bland-Ward and Moore, 1995), 7NI (5.3, Babbedge et al., 1993)

The reductase domain of NOS catalyses the reduction of cytochrome c and other redox-active dyes (Mayer and Hemmens, 1997). NADPH:O2 oxidoreductase catalyses the formation of superoxide anion/H2O2 in the absence of arginine and tetrahydrobiopterin.

Abbreviations: 1400W, N-(3-(aminomethyl) benzyl)acetamidine; NADPH, reduced nicotinamide adenosine dinucleotide phosphate; 7NI, 7-nitroindazole; NIL, L-N6-(1-iminoethyl)lysine; PIBTU, 13-phenylen-bis(1,2ethanediyl)bis-thiourea

Further Reading

Cary SP, Winger JA, Derbyshire ER, Marletta MA (2006). Nitric oxide signaling: no longer simply on or off. Trends Biochem Sci31: 231–239.

Dudzinski DM, Igarashi J, Greif D, Michel T (2006). The regulation and pharmacology of endothelial nitric oxide synthase. Annu Rev Pharmacol Toxicol46: 235–276.

Fish JE, Marsden PA (2006). Endothelial nitric oxide synthase: insight into cell-specific gene regulation in the vascular endothelium. Cell Mol Life Sci63: 144–162.

Forstermann U, Munzel T (2006). Endothelial nitric oxide synthase in vascular disease; from marvel to menace. Circulation113: 1708–1714.

Fukumura D, Kashiwagi S, Jain RK (2006). The role of nitric oxide in tumour progression. Nat Rev Cancer6: 521–534.

Jones SP; Bolli R (2006). The ubiquitous role of nitric oxide in cardioprotection. J Mol Cell Cardiol40: 16–23.

Kukreja RC, XI L (2007). eNOS phosphorylation: a pivotal molecular switch in vasodilation and cardioprotection? J Mol Cell Cardiol42: 280–282.

Moncada S, Higgs EA (2006). Nitric oxide and the vascular endothelium. Handb Exp Pharmacol176: 213–254.

Mount PF, Kemp BE, Power DA (2007). Regulation of endothelial and myocardial NO synthesis by multi-site eNOS phosphorylation. J Mol Cell Cardiol42: 271–279.

Oess S, Icking A, Fulton D, Govers R, Muller-Esterl W (2006). Subcellular targeting and trafficking of nitric oxide synthases. Biochem J396: 401–409.

Redington AE (2006). Modulation of nitric oxide pathways: therapeutic potential in asthma and chronic obstructive pulmonary disease. Eur J Pharmacol533: 263–276.

Rivero A (2006). Nitric oxide: an antiparasitic molecule of invertebrates. Trends Parasitol22: 219–225.

Sbaa E, Frerart F, Feron O (2005). The double regulation of endothelial nitric oxide synthase by caveolae and caveolin: a paradox solved through the study of angiogenesis. Trends Cardiovasc Med15: 157–162.

Tousoulis D, Boger RH, Antoniades C, Siasos G, Stefanadi E, Stefanadis C (2007). Mechanisms of disease: L-arginine in coronary atherosclerosis-a clinical perspective. Nat Clin Pract Cardiovasc Med4: 274–283.

References

Babbedge RC et al. (1993). Br J Pharmacol110: 225–228.

Bland-Ward PA, Moore PK (1995). Life Sci57: PL131-PL135.

Corbett JA, McDaniel ML (1992). Diabetes41: 897–903.

Faraci WS et al. (1996). Br J Pharmacol119: 1101–1108.

Garvey EP et al. (1994). J Biol Chem269: 26669-26676.

Garvey EP et al. (1997). J Biol Chem272: 4959–4963.

Mayer B, Hemmens B (1997). Trends Biochem Sci22: 477–481.

Moore WM et al. (1994). J Med Chem37: 3886–3888.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1-S209.

Phosphatidylcholine-specific phospholipase D (E.C. 3.1.4.4)

Overview: Phosphatidylcholine-specific phospholipase D (PLD, ENSF00000001451) catalyses the formation of phosphatidic acid from phosphatidylcholine. In addition, the enzyme can make use of alcohols, such as butanol in a transphosphatidylation reaction (Randall et al., 1990).

NomenclaturePLD1PLD2
Other namesCholine phosphatase 1Choline phosphatase 2
Ensembl IDENSG00000075651ENSG00000129219
Endogenous activatorsARF, PIP2, RhoA, PKC-evoked phosphorylation (Hammond et al., 1997)ARF, PIP2 (Lopez et al., 1998), oleic acid (Sarri et al., 2003)

A lysophospholipase D activity (ENSG00000136960, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), phosphodiesterase 1, nucleotide pyrophosphatase 2, autotaxin) has been described, which not only catalyses the production of lysophosphatidic acid from lysophosphatidylcholine, but also cleaves ATP (see Goding et al., 2003). Additionally, an N-acylethanolamine-specific phospholipase D (NAPE-PLD, ENSG00000161048) has recently been characterized, which appears to have a role in the generation of endocannabinoids/endovanilloids, including anandamide (Okamoto et al., 2004). This enzyme activity appears to be enhanced by polyamines in the physiological range (Liu et al., 2002) and fails to transphosphatidylate with alcohols (Petersen and Hansen, 1999).

Abbreviations: ARF, ADP-ribosylation factor; NAPE-PLD, N-acylethanolamine-specific phospholipase D; PIP2, phosphatidylinositol 4,5-bisphosphate

Further Reading

Becker KP, Hannun YA (2005). Protein kinase C and phospholipase D: intimate interactions in intracellular signaling. Cell Mol Life Sci62: 1448-1461.

Gomez-Cambronero J, Di Fulvio M, Knapek K (2007). Understanding phospholipase D (PLD) using leukocytes: PLD involvement in cell adhesion and chemotaxis. J Leukoc Biol82: 272–281.

Jenkins GM, Frohman MA (2005). Phospholipase D: a lipid centric review. Cell Mol Life Sci62: 2305–2316.

Klein J (2005). Functions and pathophysiological roles of phospholipase D in the brain. J Neurochem94: 1473–1487.

Morris AJ (2007). Regulation of phospholipase D activity, membrane targeting and intracellular trafficking by phosphoinositides. Biochem Soc Symp 247–257.

Oude Weernink PA, Han L, Jakobs KH, Schmidt M (2007). Dynamic phospholipid signaling by G protein-coupled receptors. Biochim Biophys Acta1768: 888–900.

Oude Weernink PA, Lopez de Jesus M, Schmidt M (2007). Phospholipase D signaling: orchestration by PIP2 and small GTPases. Naunyn-Schmiedeberg's Arch Pharmacol374: 399–411.

Ushio-Fukai M (2006). Nuclear phospholipase D1 in vascular smooth muscle: specific activation by G protein-coupled receptors. Circ Res99: 116–118.

References

Hammond SM et al. (1997). J Biol Chem272: 3860–3868.

Liu Q et al. (2002). Chem Phys Lipids115: 77–84.

Lopez I et al. (1998). J Biol Chem273: 12846–12852.

Okamoto Y et al. (2004). J Biol Chem279: 5298–5305.

Petersen G, Hansen HS (1999). FEBS Lett455: 41–44.

Randall RW et al. (1990). FEBS Lett264: 87–90.

Sarri E et al. (2003). Biochem J369: 319–329.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2); S1-S209.

Phosphodiesterases, 3′,5′-cyclic nucleotide (E.C. 3.1.4.17)

Overview: 3′,5′-Cyclic nucleotide phosphodiesterases (PDEs, 3′,5′-cyclic-nucleotide 5′-nucleotidohydrolase) catalyse the hydrolysis of a 3′,5′-cyclic nucleotide (usually cyclic AMP or cyclic GMP). IBMX is a nonselective inhibitor with an IC50 value in the millimolar range for all isoforms except PDE 8A, 8B and 9A. A 2′,3′-cyclic nucleotide 3′-phosphodiesterase (E.C. 3.1.4.37 CNPase) activity is associated with myelin formation in the development of the CNS.

NomenclaturePDE1APDE1BPDE1CPDE2A
Other namesPDE IPDE IPDE IPDE II, cGMP- stimulated
Ensembl IDENSG0000015252ENSG00000123360ENSG00000154678ENSG00000186642
Rank order of affinitycGMP > cAMPcGMP > cAMPcGMP = cAMPcAMP > > cGMP
ActivatorsCa2+/CaMCa2+/CaMCa2+/CaMcGMP
Selective inhibitorsSCH51866 (7.2, Vemulapalli et al., 1996), vinpocetine (5.1, Loughney et al., 1996)SCH51866 (7.2, Vemulapalli et al., 1996)SCH51866 (7.2, Vemulapalli et al., 1996), vinpocetine (4.3, Loughney et al., 1996)BAY607550 (8.3-8.8, Boess BAY607550 (8.3-8.8, Boess et al., 2004), EHNA (5.3, Michie et al., 1996)

PDE1A, 1B and 1C appear to act as soluble homodimers, while PDE2A is a membrane-bound homodimer. EHNA is also an inhibitor of adenosine deaminase (E.C. 3.5.4.4).

NomenclaturePDE3APDE3B
Other namesPDE III, cGMP-inhibited cAMP-PDE, CGI-PDE APDE III, cGMP-inhibited cAMP-PDE, CGI-PDE B
Ensembl IDENSG00000172572ENSG00000152270
Selective inhibitorsCilostamide (7.5, Sudo et al., 2000), milrinone (6.3, Sudo et al., 2000), cGMPCilostamide (7.3, Sudo et al., 2000), milrinone (6.0, Sudo et al., 2000), cGMP

PDE3A and PDE3B are membrane-bound.

NomenclaturePDE4APDE4BPDE4CPDE4D
Other namesPDE IVPDE IVPDE IVPDE IV
Ensembl IDENSG00000065989ENSG00000184588ENSG00000105650ENSG00000113448
Rank order of affinitycAMP > > cGMPcAMP > > cGMPcAMP > > cGMPcAMP > > cGMP
ActivatorsPKA-mediated phosphorylation (Houslay & Adams, 2003)
Selective inhibitorsRolipram (9.0, Wang et al., 1997), YM976 (8.3, Aoki et al., 2000), Ro201724 (6.5, Wang et al., 1997)Rolipram (9.0, Wang et al., 1997), Ro201724 (6.4, Wang et al., 1997)Rollipram (6.5, Wang et al., 1997), Ro201724 (5.4, Wang et al., 1997)Rolipram (7.2, Wang et al., 1997), Ro201724 (6.2, Wang et al., 1997)

PDE4 isoforms are essentially cAMP specific. The potency of YM976 at other members of the PDE4 family has not been reported. PDE4B-D long forms are inhibited by extracellular signal-regulated kinase (ERK)-mediated phosphorylation (Hoffmann et al., 1998; Hoffmann et al., 1999). PDE4A-D splice variants can be membrane-bound or cytosolic (Houslay and Adams, 2003). PDE4 isoforms may be labelled with [3H]-rolipram.

NomenclaturePDE5APDE7APDE7BPDE8APDE8B
Other namesPDE V, cGMP-specific PDEHCP1High-affinity cAMP-specific and IBMX. insensitive PDE
Ensembl IDENSG00000138735ENSG00000104732ENSG00000171408ENSG00000073417ENSG00000113231
Rank order of affinitycGMP > cAMPcGMP > > cAMP (Michaeli et al., 1993)cGMP > > cAMP (Gardner et al., 2000)cAMP > > cGMP (Fisher et al., 1998a)cAMP > > cGMP (Hayashi et al., 1998)
ActivatorsPKA (Corbin et al., 2000)
Selective inhibitorsT0156 (9.5, Mochida et al., 2002), sildenafil (9.0, Turko et al., 1999), SCH51866 (7.2, Vemulapalli et al., 1996), zaprinast (6.8, Turko et al., 1999)BRL50481 (6.7, Smith et al., 2004)Dipyridamole [5.7-6.0, Gardner et al., 2000); Sasaki et al., 2000), SCH51866 (5.8, Sasaki et al., 2000)Dipyridamole (5.1, Fisher et al., 1998a)Dipyridamole (4.3, Hayashi et al., 1998)

PDE7A appears to be membrane-bound or soluble for PDE7A1 and 7A2 splice variants, respectively. BRL50481 appears not to have been examined as an inhibitor of PDE7B.

NomenclaturePDE9APDE10APDE11A
Ensembl IDENSG00000160191ENSG00000112541ENSG00000128655
Substrate specificitycGMP > > (Fisher et al., 1998b)cAMP, cGMP (Fujishige et al., 1999)cAMP, cGMP (Fawcett et al., 2000)
Selective inhibitorsSCH51866 (5.8, Fisher et al., 1998b)
NomenclaturePDE6APDE6BPDE6CPDE6DPDE6GPDE6H
Other namescGMP-PDE α, PDE V-b1cGMP-PDE βcGMP-PDE α, PDEA2cGMP-PDE δcGMP-PDE γcGMP-PDE γ
Ensembl IDENSG00000132915ENSG00000133256ENSG00000095464ENSG00000156973ENSG00000185527ENSG00000139053

Abbreviations: BAY607550, 2-(3,4-dimethoxybenzyl)-7-[(1R)-1-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-meth ylimidazo[5,1-f][1,2,4]triazin-4(3H)-one; BRL50481, 5-nitro-2,N,N-trimethylbenzenesulfonamide; EHNA, erythro-9-(2-hydroxy-3-nonyl)adenine; PKA, cyclic AMP-dependent protein kinase; PKG, cyclic GMP-dependent protein kinase; Ro201724, 4-(3-butoxy-4-methoxyphenyl)methyl-2-imidazolidone; YM976, (4-[3-chlorophenyl]-1,7-diethylpyrido[2,3-d]pyrimidin-2(1H)-one); SCH51866, cis-5,6a,7,8,9,9a-hexahydro-2-(4-[trifluoromethyl]phenyl])-5-methyl-cyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one

Further Reading

Banner KH, Trevethick MA (2004). PDE4 inhibition: a novel approach for the treatment of inflammatory bowel disease. Trends Pharmacol Sci25: 430–436.

Bjorgo E, Tasken K (2006). Role of cAMP phosphodiesterase 4 in regulation of T-cell function. Crit Rev Immunol26: 443—451.

Boswell-Smith V, Spina D, Page CP (2006). Phosphodiesterase inhibitors. Br J Pharmacol147 (Suppl 1): S252-S257.

Castro A, Jerez MJ, Gil C, Martinez A (2005). Cyclic nucleotide phosphodiesterases and their role in immunomodulatory responses: advances in the development of specific phosphodiesterase inhibitors. Med Res Rev25: 229–244.

Fan Chung K (2006). Phosphodiesterase inhibitors in airways disease. Eur J Pharmacol533: 110–117.

Goraya TA, Cooper DMF (2005). Ca2+-calmodulin-dependent phosphodiesterase (PDE1): Current perspectives. Cell Signal17: 789–797.

Houslay MD (2005). The long and short of vascular smooth muscle phosphodiesterase-4 as a putative therapeutic target. Mol Pharmacol68: 563–567.

Houslay MD, Schafer P, Zhang KY (2005). Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today10: 1503-1519.

Lipworth BJ (2005). Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet365: 167-175.

McConnachie G, Langeberg LK, Scott JD (2006). AKAP signaling complexes: getting to the heart of the matter. Trends Mol Med12: 317-323.

O'Donnell JM, Zhang HT (2004). Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4). Trends Pharmacol Sci25: 158-163.

Sanz MJ, Cortijo J, Morcillo EJ (2005). PDE4 inhibitors as new anti-inflammatory drugs: effects on cell trafficking and cell adhesion molecules expression. Pharmacol Ther106: 269-297.

References

Aoki M et al. (2000). J Pharmacol Exp Ther295: 255–260.

Boess FG et al. (2004). Neuropharmacology47: 1081–1092.

Corbin JD et al. (2000). Eur J Biochem267: 2760–2767.

Fawcett L et al. (2000). Proc Natl Acad Sci USA97: 3702–3707.

Fisher DA et al. (1998a). Biochem Biophys Res Commun246: 570–577.

Fisher DA et al. (1998b). J Biol Chem273: 15559–15564.

Fujishige K et al. (1999). J Biol Chem274: 18438–18445.

Gardner C et al. (2000). Biochem Biophys Res Commun272: 186–192.

Hayashi M et al. (1998). Biochem Biophys Res Commun250: 751–756.

Hoffmann R et al. (1998). Biochem J333: 139–149.

Hoffmann R et al. (1999). EMBO J18: 893–903.

Houslay MD, Adams DR (2003). Biochem J370: 1–18.

Loughney K et al. (1996). J Biol Chem271: 796–806.

Michaeli T et al. (1993). J Biol Chem268: 12925–12932.

Michie AM et al. (1996). Cell Signal8: 97–110.

Mochida H et al. (2002). Eur J Pharmacol456: 91–98.

Sasaki T et al. (2000). Biochem Biophys Res Commun271: 575–583.

Smith SJ et al. (2004). Mol Pharmacol66: 1679–1689.

Sudo T et al. (2000). Biochem Pharmacol59: 347–356.

Turko IV et al. (1999). Mol Pharmacol56: 124–130.

Vemulapalli S et al. (1996). J Cardiovasc Pharmacol28: 862–869.

Wang P et al. (1997). Biochem Biophys Res Commun234: 320–324.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Phospholipase A2 (E.C. 3.1.1.4)

Overview: Phospholipase A2 (PLA2) cleaves the sn-2 fatty acid of phospholipids, primarily phosphatidylcholine, to generate lysophosphatidylcholine and arachidonic acid. Most commonly-used inhibitors (e.g. BEL, ATFMK or MAFP) are either non-selective within the family of phospholipase A2 enzymes or have activity against other eicosanoid-metabolising enzymes.

Secreted or extracellular forms

NomenclatureGIBGIIAGIIDGIIEGIIFGIII
Other namesPLA2G1B, pancreatic PLA2PLA2G2A, GIIC sPLA2, non-pancreatic secretory phospholipase A2, NPS-PLA2, synovial PLA2PLA2G2D, GIID sPLA2, secretory-type PLA2, stroma-associated homologPLA2G2E, GIIE sPLA2PLA2G2F, GIIF sPLA2GIII sPLA2
Ensembl IDENSG00000170890ENSG00000188257ENSG00000117215ENSG00000188784ENSG00000158786ENSG00000100078

PLA2G2C may be a pseudogene. A further fragment has been identified with sequence similarities to Group II PLA2 members (ENSG00000187980).

Cytosolic, calcium-dependent forms

NomenclatureGIVAGIVBGIVCGIVDGIVEGIVF
Other namesPLA2G4A, Calcium-dependent PLA2, cytosolic phospholipase A2PLA2G4B, cytosolic phospholipase A2 βPLA2G4C, cytosolic phospholipase A2 γPLA2G4D, cytosolic phospholipase A2 ωPLA2G4E, cytosolic phospholipase A2 ɛPLA2G4F, cytosolic phospholipase A2 σ
Ensembl IDENSG00000116711ENSG00000168970ENSG00000105499ENSG00000159337ENSG00000188089ENSG00000168907

PLA2-GIVA also expresses lysophospholipase (EC 3.1.1.5) activity (Sharp et al., 1994).

Other forms

NomenclatureGVGVIGVIIGXGXIIAGXIIB
Other namesPLA2G5, PLA2-10PLA2G6, Ca2+-independent, iPLA2, PNPLA9PLA2G7, LDL-associated phospholipase A2PLA2G10, GX sPLA2PLA2G12A, GXII sPLA2PLA2G12B, GXIII sPLA2-like
Ensembl IDENSG00000127472ENSG00000184381ENSG00000146070ENSG00000069764ENSG00000123739ENSG00000138308

PLA2-GVII and a close homologue (HSD-PLA2, also known as serine-dependent phospholipase A2, PAFAH2, ENSG00000158006) also express platelet-activating factor acetylhydrolase activity (EC 3.1.1.47). Otoconin 90 (OC90, ENSG00000132297) shows sequence homology to PLA2-GX.

Abbreviations: ATFMK, arachidonoyltrifluoromethylketone; BEL, bromoenolactone; MAFP, methylarachidonoylfluorophosphonate; PLA2, phospholipase A2

Further Reading

Balsinde J, Balboa MA (2005). Cellular regulation and proposed biological functions of group VIA calcium-independent phospholipase A2 in activated cells. Cell Signal17: 1052–1062.

Balsinde J, Perez R, Balboa MA (2006). Calcium-independent phospholipase A2 and apoptosis. Biochim Biophys Acta1761: 1344–1350.

Leslie CC (2004). Regulation of arachidonic acid availability for eicosanoid production. Biochem Cell Biol82: 1–17.

Lucas KK, Dennis EA (2005). Distinguishing phospholipase A2 types in biological samples by employing group-specific assays in the presence of inhibitors. Prostaglandins Other Lipid Mediat77: 235–248.

McHowat J, Creer MH (2004). Catalytic features, regulation and function of myocardial phospholipase A2. Curr Med Chem Cardiovasc Hematol Agents2: 209–218.

Reference

Sharp JD et al. (1994). J Biol Chem269: 23250–23254.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1-S209.

Phosphoinositide-specific phospholipase C (E.C. 3.1.4.11)

Overview: Phosphoinositide-specific phospholipase C (PLC) catalyses the hydrolysis of phosphatidylinositol 4,5-bisphosphate to inositol 1,4,5-trisphosphate and 1,2-diacylglycerol, each of which have major second messenger functions. Two domains, X and Y, essential for catalytic activity, are conserved in the different forms of PLC. Isoforms of PLC-β (ENSF00000000466) are activated primarily by 7TM receptors through members of the Gq/11 family of G proteins. The receptor-mediated activation of PLC-γ involves their phosphorylation by tyrosine kinases in response to activation of a variety of growth factor receptors and immune system receptors. PLC-ɛ1 may represent a point of convergence of signalling via both 7TM and catalytic receptors. Ca2+ ions are required for catalytic activity of PLC isoforms and have been suggested to be the major physiological form of regulation of PLC-δ activity. PLC has been suggested to be activated non-selectively by the small molecule m-3M3FBS (Bae et al., 2003), although this mechanism of action has been questioned (Krjukova et al., 2004). The aminosteroid U73122 has been described as an inhibitor of phosphoinositide-specific PLC (Smith et al., 1990), although its selectivity among the isoforms is untested and it has been reported to occupy the H1 histamine receptor (Hughes et al., 2000).

Nomenclatureβ1β2β3β4
Other namesPLC-I, PLC-154, KIAA0581
Ensembl IDENSG00000182621ENSG00000137841ENSG00000149782ENSG00000101333
Endogenous activatorsGαq (Smrcka et al., 1991; Hepler et al., 1993), Gα11 (Hepler et al., 1993), Gβγ (Park et al., 1993)Gα16 (Lee et al., 1992), Gβγ (Camps et al., 1992; Park et al., 1993)Gαq (Lee et al., 1992), Gβγ (Carozzi et al., 1993; Park et al., 1993)Gαq (Jhon et al., 1993)
Nomenclatureγ1γ2δ1δ3δ4
Other namesPLC-II, PLC-148PLC-IVPLC-III
Ensembl IDENSG00000124181ENSG00000197943ENSG00000187091ENSG00000161714ENSG00000115556
Endogenous activatorsPtdIns 3,4,5-P3 (Bae et al., 1998)PtdIns 3,4,5-P3 (Bae et al., 1998)Transglutaminase II (Murthy et al., 1999), p122-RhoGAP (Homma and Emori, 1995), spermine (Haber et al., 1991), Gβγ (Park et al., 1993)
InhibitorsSphingomyelin (Pawelczyk and Lowenstein, 1992)

PLC-δ2 has been cloned from bovine sources (Meldrum et al., 1991).

Nomenclatureɛ1ζ1η1η2
Other namesPancreas-enriched PLC
Ensembl/GenBank IDENSG00000138193ENSG00000139151AY691170 (Hwang et al., 2005)DQ176850 (Zhou et al., 2005) Gβγ (Zhou et al., 2005)
Endogenous activatorsRas (Song et al., 2001), Rho (Wing et al., 2003) 

A series of PLC-like proteins (PLCL1 ENSG00000115896; PLCL2 ENSG00000154822 and PLCL3 ENSG00000114805) form a family (ENSF00000000386) with PLCδ and PLCζ1 isoforms, but appear to lack catalytic activity.

Abbreviations: m-3M3FBS, 2,4,6-trimethyl-N-(meta-3-trifluoromethylphenyl)-benzenesulphonamide; Ptdlns 3,4,5-P3, phosphatidylinositol 3,4,5-trisphosphate; U73122, 1-(6-[{(17β)-3-methoxyestra-1,3,5[10]-trien-17-yl}amino]hexyl)-1H-pyrrole-2,5-dione

Further Reading

Bunney TD, Katan M (2006). Phospholipase Ca: linking second messengers and small GTPases. Trends Cell Biol16: 640–648.

Cocco L, Faenza I, Fiume R, Maria BA, Gilmour RS, Manzoli FA (2006). Phosphoinositide-specific phospholipase C (PI-PLC) β1 and nuclear lipid-dependent signaling. Biochim Biophys Acta1761: 509–521.

Cockcroft S (2006). The latest phospholipase C, PLCη, is implicated in neuronal function. Trends Biochem Sci31: 4–7.

Drin G, Scarlata S (2007). Stimulation of phospholipase Cβ by membrane interactions, interdomain movement, and G protein binding. How many ways can you activate an enzyme? Cell Signal19: 1383–1392.

Harden TK, Sondek J (2006). Regulation of phospholipase C isozymes by ras superfamily GTPases. Annu Rev Pharmacol Toxicol46: 355–379.

Oude Weernink PA, Han L, Jakobs KH, Schmidt M (2007). Dynamic phospholipid signaling by G protein-coupled receptors. Biochim Biophys Acta1768: 888–900.

References

Bae YS et al. (1998). J Biol Chem273: 4465–4469.

Bae YS et al. (2003). Mol Pharmacol63: 1043–104.

Camps M et al. (1992). Nature360: 684–686.

Carozzi A et al. (1993). FEBS Lett315: 340–342.

Haber MT et al. (1991). Arch Biochem Biophys288: 243–249.

Hepler JR et al. (1993). J Biol Chem268: 14367–14375.

Homma Y, Emori Y (1995). EMBO J14: 286–291.

Hughes SA et al. (2000). Naunyn-Schmiedeberg's Arch Pharmacol362: 555–558.

Hwang JI et al. (2005). Biochem J389: 181–186.

Jhon D-Y et al. (1993). J Biol Chem268: 6654–6661.

Krjukova J et al. (2004). Br J Pharmacol143: 3–7.

Lee CH et al. (1992). J Biol Chem267: 16044–16047.

Meldrum E et al. (1991). Eur J Biochem196: 159–165.

Murthy SNP et al. (1999). Proc Natl Acad Sci USA96: 11815–11819.

Park D et al. (1993). J Biol Chem268: 4573–4576.

Pawelczyk T, Lowenstein JM (1992). Arch Biochem Biophys297: 328–333.

Smith RJ et al. (1990). J Pharmacol Exp Ther253: 688–697.

Smrcka AV et al. (1991). Science251: 804–807.

Song C et al. (2001). J Biol Chem276: 2752–2757.

Wing MR et al. (2003). Mol Interv3: 273–280.

Zhou Y et al. (2005). Biochem J391: 667–676.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1-S209.

Protein serine/threonine kinases (E.C. 2.7.1.37)

Overview: Protein serine/threonine kinases use the co-substrate ATP to phosphorylate serine and/or threonine residues on target proteins. Most inhibitors of these enzymes have been assessed in cell-free investigations and so may appear to ‘lose’ potency and selectivity in intact cell assays. In particular, ambient ATP concentrations may be influential in responses to inhibitors, since the majority are directed at the ATP binding site (see Davies et al., 2000; Bain et al., 2007).

It is beyond the scope of the Guide to list all protein kinase activities; this summary focusses on protein kinases involved in signalling from 7-transmembrane receptors.

NomenclatureProtein kinase AProtein kinase BProtein kinase GRho kinase
Preferred abbreviationPKAPKBPKG
Other namesCyclic AMP-dependent protein kinaseAktCyclic GMP-dependent protein kinaseP160ROCK, Rho-activated kinase
Ensembl IDRegulatory subunits: PRKAR1A(ENSG00000108946); PRKAR1B (ENSG00000188191); PRKAR2A (ENSG00000114302); PRKAR2B (ENSG00000005249); Catalytic subunits: PRKACA (ENSG00000072062); PRKACB (ENSG00000142875); PRKACG (ENSG00000165059)AKT1 (ENSG00000142208); AKT2 (ENSG00000105221); AKT3 (ENSG00000117020)PRKG1 (ENSG00000185532); PRKG2 (ENSG00000138669)ROCK1 (ENSG00000067900); ROCK2 (ENSG00000134318)
Endogenous activatorcAMPPDK1 (Alessi et al., 1997)cGMPRho
Selective activatorsN6-Benzyl-cAMP (Christensen et al., 2003)
Selective inhibitorsRp-cAMPSRp-8-CPT-cGMPS (Butt et al., 1994)Y27632 (Uehata et al., 1997), fasudil (Asano et al., 1989)
Probes[3H]-cAMP

PKA is a heterotetrameric enzyme composed of two regulatory and two catalytic subunits, which can be distinguished from Epac (exchange protein directly activated by cAMP, de Rooij et al., 1998) by differential activation by N6-benzyl-cAMP and CPT-2′OMe-cAMP, respectively (Kang et al., 2005). AKT1 and AKT2 can be selectively inhibited by AKT 1/2 inhibitor with pIC50 values of 7.3 and 6.8, respectively (Zhao et al., 2005), while deguelin (Chun et al., 2003), API2 (Yang et al., 2004) and Akt inhibitor IV (Kozikowski et al., 2003) can inhibit PKB activity by inhibiting activation by upstream kinases.

Protein kinase C

Protein kinase C is the target for the tumour-promoting phorbol esters, such as tetradecanoyl-β-phorbol acetate (TPA). Classical protein kinase C isoforms: Members of the classical protein kinase C family are activated by Ca2+ and diacylglycerol, and may be inhibited by GF109203X, calphostin C, Gö6983, chelerythrine and Ro318220.

NomenclaturePKCαPKCβ1PKCβ2PKCγ
Other namesPRKCAPRKCB1PRKCB2PRKCG
Ensembl IDENSG00000154229ENSG00000166501ENSG00ENSG00000126583
Selective inhibitorsRuboxistaurin (8.3, Jirousek et al., 1996), CGP53353 (6.4, Chalfant et al., 1996)Ruboxistaurin (8.2, Jirousek et al., 1996)

Novel protein kinase C isoforms: Members of the classical protein kinase C family are activated by diacylglycerol and may be inhibited by calphostin C, Gö6983 and chelerythrine.

NomenclaturePKCδPKCɛPKCηPKCθPKCμ
Other namesPRKCDPRKCEPRKCHPRKCQKPCD1, nPKC-D1, protein kinase D
Ensembl IDENSG00000163932ENSG00000171132ENSG00000027075ENSG00000065675ENSG00000184304

Atypical protein kinase C isoforms

NomenclaturePKCζPKClPKN
Other namesPRKCZPRKCI (PKCλ in rodents)PRK, Protein kinase N1, protein kinase C-related kinase 1
Ensembl IDENSG00000067606ENSG00000163558ENSG00000123143
Endogenous activatorArachidonic acidRho, PIP3

Mitogen-activated protein kinases (MAP kinases)

NomenclatureERK1ERK2JNK1JNK2JNK3
HUGO NomenclatureMAPK3MAPK1MAPK8MAPK9MAPK10
Other namesInsulin-stimulated MAP2 kinase, ERT2, p44-MAPK, Microtubule-associated protein-2 kinaseMitogen-activated protein kinase 2, p42-MAPK, ERT1SAPK1, c-Jun N-terminal kinase 1, JNK-46c-Jun N-terminal kinase 2, JNK-55c-Jun N-terminal kinase 3, MAP kinase p49 3F12
Ensembl IDENSG00000102882ENSG00000100030ENSG00000107643ENSG00000050748ENSG00000109339
Endogenous activatorMAP2K1, MAP2K2MAP2K1, MAP2K2MAP2K4, MAP2K7MAP2K4, MAP2K7MAP2K4, MAP2K7
Selective inhibitorsSP600125 (6.7, Bennett et al., 2001)SP600125 (6.7, Bennett et al., 2001)SP600125 (6.7, Bennett et al., 2001)

MAP kinases (CMGC kinases, ENSF00000000137) may be divided into three major families: ERK1/2, JNK and p38 MAP kinases.

The inhibitors PD98059 (Alessi et al., 1995; Dudley et al., 1995) and U0126 (Duncia et al., 1998; Favata et al., 1998) are used as selective inhibitors of ERK1 and ERK2, but have been shown rather to target the upstream kinase cascade (Davies et al., 2000).

MAP2K1 (ENSG00000169032, EC 2.7.12.2) and MAP2K2 (ENSG00000126934, EC 2.7.12.2) are also known as MAP kinase kinase 1 and 2, or MEK1 and MEK2, respectively. MAP2K4 (ENSG00000065559, EC 2.7.12.2) and MAP2K7 (ENSG00000076984, EC 2.7.12.2) are also known as JNK-activating kinase 1 and 2 or JNKK1 and JNKK2, respectively.

Nomenclaturep38αp38βp38γp38δ
HUGO NomenclatureMAPK14MAPK11MAPK12MAPK13
Other namesCytokine suppressive anti-inflammatory drug binding protein, MAX-interacting protein 2p38-2, SAPK2ERK-6, ERK5, SAPK3SAPK4
Ensembl IDENSG00000112062ENSG00000185386ENSG00000188130ENSG00000156711
Endogenous activatorMAP2K3, MAP2K6MAP2K3, MAP2K6MAP2K3, MAP2K6MAP2K3, MAP2K6
Selective inhibitorsSB203580 (8.0, Eyers et al., 1998)SB203580 (7.0 Eyers et al., 1998)

MAP2K3 (ENSG00000034152, EC 2.7.12.2) and MAP2K6 (ENSG00000108984, EC 2.7.12.2) are also known as MAP kinase kinase 3 and MAP kinase kinase 6, respectively.

Selected other protein kinase activities

NomenclatureAMP kinaseMyosin light chain kinase 1Myosin light chain kinase 2Calmodulin-dependent kinase II
Preferred abbreviationAMPKMLCK1MLCK2CaMKII
Other namesMYLK, smooth muscle and non-muscle isoformMYLK, skeletal muscle isoform
Ensembl IDα1 (ENSG00000132356);ENSG00000065534ENSG00000101306α (ENSG00000070808);
 α2 (ENSG00000162409);  β (ENSG00000058404);
 β1 (ENSG00000111725);  γ (ENSG00000148660);
 β2 (ENSG00000131791);  δ (ENSG00000145349)
 γ1 (ENSG00000181929),   
 γ2 (ENSG00000106617);   
 γ3 (ENSG00000115592)   
Endogenous activatorAMPCa2+-calmodulinCa2+-calmodulinCa2+-calmodulin
Selective activatorsAICA-riboside Corton et al. (1995)

AMP-activated protein kinase is a heterotrimeric protein kinase, made up of α, β and γ subunits. STO609 is an inhibitor of calmodulin kinase kinase (EC 2.7.11.17, Tokumitsu et al., 2002), an upstream activator of calmodulin-dependent kinase.

Abbreviations: AICA-riboside, 5-aminoimidazole-4-carboxamide-1-β-riboside, also known as acadesine; AKT1/2, 1,3-dihydro-1-(1-[{4-(6-phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl) phenyl}methyl]-4-piperidinyl)-2H-benzimidazol-2-one trifluoroacetate salt hydrate; Akt inhibitor IV, 5-(2-benzothiazolyl)-3-ethyl-2-(2-[methylphenylamino] ethenyl)-1-phenyl-1H-benzimidazolium iodide; API2, 1,5-dihydro-5-methyl-1-β-D-ribofuranosyl-1,4,5,6,8- pentaazaacennaphthylen-3-amine, also known as triciribine; CGP53353, 5,6-bis([4-fluorophenyl]amino)-2H-isoindole-1,3-dione; CPT-2′-OMe-cAMP, 8-(4-chlorophenylthio)-2-O-methyladenosine 3,5-cyclic monophosphate monosodium hydrate; fasudil, 1-(5-isoquinolinylsulfonyl)homopiperazine dihydrochloride, also known as HA1077; PD98059, 2-(2-amino-3-methoxy-phenyl)chromen-4-one; PDK1, 3-phosphoinoisitide-dependent protein kinase 1 (EC 2.7.11.1) ENSG00000140992; Rp-8-CPT-cGMPS, Rp-8-[(4-chlorophenyl)thio]-guanosine-cyclic 3,5-hydrogen phosphorothioate; ruboxistaurin, (S)-13-[(dimethylamino)methyl] −10,11,14,15-tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo [e,k]pyrrolo[3,4-h][1,4,13] oxadiazacyclohexadecene-1,3(2H)-dione, also known as LY333531; SB203580, 4-(5-[4-fluorophenyl]-2-[4-methylsulfinylphenyl]-3H-imidazol-4-yl) pyridine; SP600125, anthra[1,9-cd]pyrazol-6(2H)-one; STO609, 7-oxo-7H-benzimidazo(2,1a) benz(de)isoquinoline-3-carboxy acid acetate; Y27632, (R)-(+)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride monohydrate

Further Reading

Arad M, Seidman CE, Seidman JG (2007). AMP-activated protein kinase in the heart: role during health and disease. Circ Res100: 474–488.

Ashwell JD (2006). The many paths to p38 mitogen-activated protein kinase activation in the immune system. Nat Rev Immunol6: 532–540.

Bain J, Plater L, Elliott M, Shpiro N, Hastie J, McLauchlan H et al. (2007). The selectivity of protein kinase inhibitors; a further update. Biochem J (in press).

Bolos J (2005). Structure-activity relationships of p38 mitogen-activated protein kinase inhibitors. Mini Rev Med Chem5: 857–868.

Caplan AJ, Mandal AK, Theodoraki MA (2007). Molecular chaperones and protein kinase quality control. Trends Cell Biol17: 87–92.

Cuevas BD, Abell AN, Johnson GL (2007). Role of mitogen-activated protein kinase kinase kinases in signal integration. Oncogene26: 3159–3171.

Daval M, Foufelle F, Ferre P (2006). Functions of AMP-activated protein kinase in adipose tissue. J Physiol574: 55–62.

Davies SP, Reddy H, Caivano M, Cohen P (2000). Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J351: 95–105.

Fayard E, Tintignac LA, Baudry A, Hemmings BA (2005). Protein kinase B/Akt at a glance. J Cell Sci118: 5675–5678.

Griner EM, Kazanietz MG (2007). Protein kinase C and other diacylglycerol effectors in cancer. Nat Rev Cancer7: 281–294.

Hardie DG (2007). AMP-activated protein kinase as a drug target. Annu Rev Pharmacol Toxicol47: 185–210.

Hardie DG, Hawley SA, Scott JW (2006). AMP-activated protein kinase—development of the energy sensor concept. J Physiol574: 7–15.

Hool LC (2005). Protein kinase C isozyme selective peptides—a current view of what they tell us about location and function of isozymes in the heart. Curr Pharm Des11: 549–559.

Hund TJ, Rudy Y (2006). A role for calcium/calmodulin-dependent protein kinase II in cardiac disease and arrhythmia. Handb Exp Pharmacol 201–220.

Katsoulidis E, Li Y, Mears H, Platanias LC (2005). The p38 mitogen-activated protein kinase pathway in interferon signal transduction. J Interferon Cytokine Res25: 749–756.

Liao JJ (2007). Molecular recognition of protein kinase binding pockets for design of potent and selective kinase inhibitors. J Med Chem50: 409–424.

Malemud CJ (2007). Inhibitors of stress-activated protein/mitogen-activated protein kinase pathways. Curr Opin Pharmacol7: 339–343.

Manning BD, Cantley LC (2007). AKT/PKB signaling: navigating downstream. Cell129: 1261–1274.

Meloche S, Pouyssegur J (2007). The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene26: 3227–3239.

Perletti G, Terrian DM (2006). Distinctive cellular roles for novel protein kinase C isoenzymes. Curr Pharm Des12: 3117–3133.

Roberts PJ, Der CJ (2007). Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene26: 3291–3310.

Rockey WM, Elcock AH (2006). Rapid computational identification of the targets of protein kinase inhibitors. Curr Opin Drug Discov Devel9: 326–331.

Rozengurt E, Rey O, Waldron RT (2005). Protein kinase D signaling. J Biol Chem280: 13205–13208.

Salamanca DA, Khalil RA (2005). Protein kinase C isoforms as specific targets for modulation of vascular smooth muscle function in hypertension. Biochem Pharmacol70: 1537–1547.

Schillace RV, Carr DW (2006). The role of protein kinase A and A-kinase anchoring proteins in modulating T-cell activation: progress and future directions. Crit Rev Immunol26: 113–131.

Shen K, Hines AC, Schwarzer D, Pickin KA, Cole PA (2005). Protein kinase structure and function analysis with chemical tools. Biochim Biophys Acta1754: 65–78.

Soltoff SP (2007). Rottlerin: an inappropriate and ineffective inhibitor of PKCδ. Trends Pharmacol Sci28: 453–458.

Stambolic V, Woodgett JR (2006). Functional distinctions of protein kinase B/Akt isoforms defined by their influence on cell migration. Trends Cell Biol16: 461–466.

Steinberg GR, Jorgensen SB (2007). The AMP-activated protein kinase: role in regulation of skeletal muscle metabolism and insulin sensitivity. Mini Rev Med Chem7: 519–526.

Thompson JE (2005). JAK protein kinase inhibitors. Drug News Perspect18: 305–310.

Towler MC, Hardie DG (2007). AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res100: 328–341.

Ubersax JA, Ferrell JE (2007). Mechanisms of specificity in protein phosphorylation. Nat Rev Mol Cell Biol8: 530–541.

Westra J, Limburg PC (2006). p38 mitogen-activated protein kinase (MAPK) in rheumatoid arthritis. Mini Rev Med Chem6: 867–874.

Woodgett JR (2005). Recent advances in the protein kinase B signaling pathway. Curr Opin Cell Biol17: 150–157.

Young LH, Li J, Baron SJ, Russell RR (2005). AMP-activated protein kinase: a key stress signaling pathway in the heart. Trends Cardiovasc Med15: 110–118.

References

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Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Soluble guanylyl cyclase (E.C. 4.6.1.2)

Overview: Soluble guanylyl cyclase (GTP diphosphate-lyase (cyclising)) is a heterodimer comprising α and β chains, both of which have two subtypes in man (predominantly α1β1; see Zabel et al., 1998). A haem group is associated with the b chain and is the target for the endogenous ligand nitric oxide (NO), and, potentially, carbon monoxide (Friebe et al., 1996). The enzyme converts guanosine-5′-triphosphate (GTP) to the intracellular second messenger 3′,5′-guanosine monophosphate (cGMP).

NomenclatureSoluble guanylyl cyclase
Preferred abbreviationsGC
Ensembl IDα1 ENSG00000164116; α2 ENSG00000152402; β1 ENSG00000061918; β2 ENSG00000123201
Selective activatorsNO, YC1 (Friebe et al., 1996), BAY412272 (Stasch et al., 2001), BAY582667 (Stasch et al., 2002)
Selective inhibitorsODQ (7.5; Garthwaite et al., 1995)

ODQ also shows activity at other haem-containing proteins (Feelisch et al., 1999), while YC1 may also inhibit cGMP-hydrolysing phosphodiesterases (Friebe et al. 1998; Galle et al., 1999).

Abbreviations: BAY412272, 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine); BAY582667, 4-([4-carboxybutyl][2-{(4-phenethylbenzyl)oxy}phenethyl]amino)methyl(benzoic)acid; ODQ, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; YC1, 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole HMR1766

Further Reading

Cary SP, Winger JA, Derbyshire ER, Marletta MA (2006). Nitric oxide signaling: no longer simply on or off. Trends Biochem Sci31: 231–239.

Cerra MC, Pellegrino D (2007). Cardiovascular cGMP-generating systems in physiological and pathological conditions. Curr Med Chem14: 585–599.

Doggrell SA (2005). Clinical potential of nitric oxide-independent soluble guanylate cyclase activators. Curr Opin Investig Drugs6: 874–878.

Evgenov OV, Pacher P, Schmidt PM, Hasko G, Schmidt HH, Stasch JP (2006). NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov5: 755–768.

Jackson EB, Mukhopadhyay S, Tulis DA (2007). Pharmacologic modulators of soluble guanylate cyclase/cyclic guanosine monophosphate in the vascular system—from bench top to bedside. Curr Vasc Pharmacol5: 1–14.

Moncada S, Higgs EA (2006). Nitric oxide and the vascular endothelium. Handb Exp Pharmacol176: 213–254.

Poulos TL (2006). Soluble guanylate cyclase. Curr Opin Struct Biol16: 736–743.

Pyriochou A, Papapetropoulos A (2005). Soluble guanylyl cyclase: more secrets revealed. Cell Signal17: 407–413.

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Feelisch M et al. (1999). Mol Pharmacol56: 243–253.

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Stasch JP et al. (2002). Br J Pharmacol136: 773–783.

Citation Information

We recommend that any citations to information in the Guide are presented in the following format:

Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol153 (Suppl. 2): S1–S209.

Ancillary