Glycolysis is the anaerobic breakdown of sugar to pyruvate; gluconeogenesis is the formation of D-glucose from compounds which are not carbohydrates.
Some accounts of the following scientists, who are mentioned here, are given in earlier articles of this series: C. F. Cori , E. Fischer , E. F. Gale , J. S. Haldane, D. Keilin, E. P. Kennedy , A. J. Kluyver , H. A. Krebs , A. L. Lehninger , F. A. Lipmann , B. Magasanik , O. F. Meyerhof , J. Monod , P. Ostern , L. Pasteur , A. Sols , S. Spiegelman , A. von Szent-Györgyi , O. Warburg .
Dean Burk (1904–1988), American biochemist, worked at University College London, the Kaiser Wilhelm Institute in Berlin and Harvard and Cornell Universities. He became chief chemist at the National Cancer Institute, Bethesda .
Kendal Cartwright Dixon (1911–1990), Irish biochemist and medical man, worked on carbohydrate and lipid metabolism in Cambridge from 1933, where he became Professor of Cellular Pathology .
Si l'expérience est faite au contact de l'air et sur une grande surface…Pour la même quantité de sucre disparu, il se fait beaucoup plus de levûre. L'air en contact cède de l'oxygène qui est absorbé par la levûre. Celle-ci se développe énergiquement, mais son caractère de ferment tend à disparaître dans ces conditions. On trouve en effet que pour 1 partie de levûre formée, il n'y aura que 4 à 10 parties de sucre transformé. Le rôle de ferment de cette levûre subsiste néanmoins et se montre même fort exalté si l'on vient à la faire agir sur le sucre en dehors de l'influence du gaz oxygène libre [282, p. 80].
Atmung und Gärung sind also durch eine chemische Reaktion verbunden, die ich nach ihrem Entdecker ‘Pasteursche Reaktion’ nenne [367, p. 435].
Warburg manometers are described in article 5 of this series [23, p. 516].
Q and Q were expressed as mm3 of O2 taken up or of CO2 produced, respectively, per mg dry weight of yeast per hour.
Archibald Vivian Hill (1886–1977), English physiologist, was professor first at Manchester University from 1923, then at University College London from 1926. He shared the 1922 Nobel Prize for physiology or medicine with Otto Meyerhof for work on heat production in muscle contraction .
James Lorrain Smith (1862–1931), Scottish physiologist, worked at Oxford with J. S. Haldane on air pollution caused by breathing. He moved to Queen's College, Belfast, in 1894, where he became professor in 1901. Subsequently he held chairs in Manchester and Edinburgh .
Hans Laser (1899–1980), German biochemist, worked at the Kaiser Wilhelm Institute for Cell Physiology at Berlin, but came to England as a refugee from the Nazi government in 1934. He worked for over 30 years at the Molteno Institute, Cambridge, where his research included a study of lysis of cells in patients with malaria and the study of neoplastic cells .
Vladimir Alexandrovich Engelhardt (1894–1984) was a great and much-liked Russian biochemist, who discovered oxidative phosphorylation and the functioning of myosin as an ATPase. He was professor of biochemistry at Kazan University from 1929 and from 1935 at the Institute of Biochemistry of the Academy of Sciences of the USSR in Moscow whence, in the early 1940s when the war was approaching Moscow, he was evacuated to Kazakhstan in Central Asia   .
Nikolai E. Sakov died in the battle for Stalingrad in 1942, his joint work with Engelhardt having been completed in 1941  .
6-Phosphofructokinase was discovered in 1936 by Pawel Ostern and his colleagues , see .
Redox dyes are mostly coloured when oxidized and colourless when reduced. Engelhardt and Sakov found inhibition by dyes with E′0 > +0.05 V, such as 2,6-dibromophenolindophenol or 2,6-dichlorophenolindophenol. E′0 is the approximate electrode potential, when there are equal concentrations of both oxidized and reduced forms at pH 7. Relations of the oxidation–reduction (‘redox’) potential, electromotive force and ionic concentration had been worked out in 1889 by Hermann Walther Nernst (1864–1941) .
Joseph Lewis Melnick (1914–2001), American medical microbiologist, worked especially on enteroviruses at Yale University. He became Professor of epidemiology in 1954 (Historical Register of Yale University, 1951–1968, p. 523) and moved to a chair at Baylor College of Medicine, Houston, in 1958   .
S. cerevisiae has two enzymes that phosphorylate D-fructose 6-phosphate. The best known glycolytic enzyme, named 6-phosphofructokinase-1, is a heterooctamer with 4 α- and 4 β-subunits , which are encoded by genes PFK1 (α-subunit) and PFK2 (β-subunit)  . 6-Phosphofructokinase-1 phosphorylates D-fructose 6-phosphate to the glycolytic intermediate fructose 1,6-bisphosphate, whereas 6-phosphofructokinase-2 (encoded by PFK26 and PFK27) phosphorylates D-fructose 6-phosphate to D-fructose 2,6-bisphosphate.
R. H. De Deken (1927–?) worked on yeast biochemistry and biochemical cytology at the Institut de Recherches du Centre d'Enseignement et de Recherches des Industries Alimentaires et Chimiques (Brussels) in the 1950s and 1960s.
Walter Bartley (1916–1994), English biochemist, worked in Hans Krebs' laboratory, first in Sheffield and then in Oxford as a technician and later as a research student. Bartley became deputy director of Krebs' Medical Research Council Unit for Cell Metabolism at Oxford and returned to Sheffield in 1963 as professor of biochemistry   .
Mitochondria, the sites in eukaryotes of tricarboxylic acid cycle reactions and oxidative phosphorylation (see ).
Arthur A. Andreasen, who worked with Stier at Bloomington, was with Lynferd Wickerham in the early 1940s at the University of Illinois, Urbana, working on preserving yeasts by freeze-drying for the degree of Master of Science .
Theodore James Blanchard Stier (1903–1991), American cellular physiologist, was professor of physiology at Indiana University from 1947 (information kindly supplied by Kristen Walker of Indiana University Archives).
Mathieu Theodoor Jozef Custers, Dutch microbiologist, defended his doctor's thesis on 3 May 1940, 1 week before the German army invaded The Netherlands. He became a school teacher in Amsterdam and died before 1970 (W. A. Scheffers, personal communication).
Acetoin (3-hydroxy-2-butanone) may be reduced to butane-2,3-diol by the action of butanediol dehydrogenase: CH3·CO·CH(OH)·CH3 + NADH + H+→CH3·CH(OH)·CH(OH)·CH3 + NAD+ .
As described for bacterial acetate production, such as by Pseudomonas fluorescens .
In 1922, Richard Willstätter (1872–1942) and Gertrud Oppenheimer (1893–1948) had disputed Fischer's view . They found that certain yeasts ferment lactose more rapidly than they ferment D-glucose, D-galactose or an equimolar mixture of the two and, hence, concluded that the first metabolic step is not necessarily hydrolytic. Their evidence for ‘direct’ fermentation of oligosaccharides remained a matter of dispute (e.g.  ) until 1949, when Alfred Gottschalk pointed out that the rate of entry of a sugar across the plasma membrane might limit the rate of catabolism of that sugar .
Anthony Peter Sims (1933–1990), English biochemist, worked at the University of East Anglia, Norwich on the regulation of metabolism in Candida utilis, other fungi and green plants .
Whereas maltose (4-O-α-D-glucopyranosyl-D-glucopyranose) is an α-linked glucose-glucose disaccharide, cellobiose (4-O-β-D-glucopyranosyl-D-glucopyranose) is the same, but β-linked:
Generally hydrolysed in the cytosol: maltose, cellobiose, lactose, melezitose and methyl α-D-glucopyranoside. Generally hydrolysed outside the plasma membrane: raffinose and melibiose .
The mutant was defective in glucose repression and had uncontrolled uptake of maltose .
TMG (methyl 1-thio-β-D-galactopyranoside) was used by Adam Kepes for studying the kinetics of β-galactoside transport into Escherichia coli in the 1950s  (see also ).
Facilitated diffusion is carrier-mediated movement across a membrane which, unlike active transport, depends on a concentration gradient and not on expenditure of metabolic energy (for review see ).
Two β-glucosidases of Debaryomyces polymorphus have Km = 22 mM and 40 mM-cellobiose, respectively .
Herbert Grace Crabtree (1892–1966), English biochemist, was with the Imperial Cancer Research Fund in London for 43 years .
Wilbur H. Swanson (1903–?) worked with Charles Clifton at the Department of Bacteriology and Experimental Pathology, School of Medicine, Stanford University, California in the 1940s, moving to San Jose State College in 1948.
Charles Egolf Clifton (1904–1976), American microbial biochemist, worked at the Department of Bacteriology and Experimental Pathology, School of Medicine, Stanford University from 1929, becoming professor of bacteriology (information kindly supplied by Patricia A. French of Lane Medical Library, Archives and Special Collection Department, Stanford University, School of Medicine).
Sodium azide (NaN3) prevents the coupling of ADP phosphorylation to aerobic respiration ; in 1949, Eugene Kennedy and Albert Lehninger found that isolated mitochondria catalyse oxidative phosphorylation, which is coupled to the oxidation of intermediates of the tricarboxylic acid cycle .
Glyoxylate cycle (a modification of the tricarboxylic acid cycle) by which two molecules of acetate form one molecule of C4-dicarboxylic acid, occurs not only in yeasts, but also in bacteria (e.g. ), filamentous fungi (e.g.  ) and green plants (e.g. ).
The glyoxylate cycle was first described by Kornberg, Krebs and Madsen in 1957  . In 1960, Barnett and Kornberg published evidence of its occurrence in the yeasts, Kluyveromyces lactis, Saccharomyces cerevisiae and Zygosaccharomyces bailii . However, Schizosaccharomyces pombe is said to lack two key enzymes of the cycle , which may explain its reported inability to utilize acetate as sole carbon source for growth [207, p. 345].
cAMP, cyclic AMP, adenosine 3′, 5′-cyclic monophosphate, is formed from ATP in a reaction catalysed by adenylate cyclase and has regulatory functions in many kinds of organism. cAMP was first reported in a yeast in 1966 .
The cAMP receptor protein is also named CAP (for catabolite gene activator protein).
Understanding the molecular basis of glucose repression became possible in the 1970s with the development of methods of gene isolation and sequencing. The first yeast gene was probably cloned in 1976  and yeast transformations were reported in 1978  . Accordingly, in the 1980s, many genes corresponding to glucose-repression mutants were isolated and their sequences determined.
For ease of reading, gene synonyms are given in brackets where original findings are reported and, thereafter, preference is given to the gene name which has been first sequenced.
Michael Ciriacy (1947–1996), German geneticist, studied the regulation of alcohol dehydrogenase isoenzymes, showed the first Ty1 retrotransposon integration to be responsible for constitutive adh2 expression, and characterized glucose carriers of Saccharomyces cerevisiae genetically. He was in Fritz Zimmermann's laboratory at Darmstadt from 1977 to 1981, when he became a professor at the Institute of Microbiology at the University of Düsseldorf .
Abbreviations used for proteins, for which each gene is responsible, are written as the abbreviation of gene's name, printed in roman type, with the first letter a capital, e.g. Adh1. This may also be written Adh1p: the ‘p’ is added (for protein) to prevent misunderstanding. This convention differs from that used for the genes; e.g. the wild-type structural gene of alcohol dehydrogenase I is written ADH1 (in italic capitals) and a mutant is adh1 (italic lower case).
A promoter is a DNA region upstream to the coding sequence of a gene, which binds RNA polymerase.
Alcohol dehydrogenase II (Adh2p), encoded by the gene ADH2, catalyses the first step of gluconeogenesis from ethanol. Adh2p is cytoplasmic, necessary for alcohol degradation and is repressed by glucose several hundred-fold .
A pleiotropic mutation has more than one phenotypic effect.
Alcohol dehydrogenase I (Adh1p), unlike Adh2p, is the enzyme responsible for the formation of ethanol in ‘alcoholic fermentation’.
Fructose bisphosphatase (D-fructose-1,6-bisphosphate 1-phosphohydrolase, EC 18.104.22.168) is often written ‘fructose-1,6-bisphosphatase’ in order to distinguish it clearly from fructose-2,6-bisphosphate 2-phosphatase, EC 22.214.171.124, (also written ‘fructose-2,6-bisphosphatase’). Fructose bisphosphatase catalyses D-fructose 1, 6-bisphosphate + H2O→D-fructose 6-bisphosphate + ortho-phosphate. Fructose bisphosphatase was first prepared from kidney and liver in 1943 by George Gomori  and its specificity for fructose 1,6-bisphosphate was reported in 1955 .
Pabitra K. Maitra (b. 1932), Indian biochemist and geneticist, worked at the Tata Institute of Fundamental Research in Bombay (Mumbai). Together with Zita Lobo, he made major contributions to the genetics and biochemistry of yeast carbohydrate metabolism.
Zita Lobo (?–2000), Indian biochemist, was married to P. K. Maitra, with whom she published most of her 23 papers on carbohydrate metabolism and genetics of yeasts .
In the 1960s, Saccharomyces cerevisiae was found to have two distinct hexokinase isoenzymes, PI and PII   .
The physical interaction of SNF1 and SNF4 was used to establish the yeast two-hybrid system , which is even today an effective method for obtaining first indications of physical protein–protein interactions and is used in functional genome analyses for many species.
GCL7 is an essential gene. Originally, a mutant with non glucose-repressible invertase was isolated and called cid1 (for constitutive invertase derepression) . Later analysis of this mutant showed it to be viable (T152K) within the GLC7 gene .
Fields and Song made use of the characteristics of the transcriptional activator protein GAL4p of Saccharomyces cerevisiae . This activator has functional domains for DNA binding (Gal4p-BD) and for gene activation (Gal4p-AD), which Fields and Song separated as two genes. Gal4p-BD is fused to one protein, X, and Gal4p-AD to protein Y. If X and Y interact to form a dimer, this dimerization brings the Gal4p-AD and Gal4p-BD together. As a result, transcription of genes regulated by GAL4p DNA-binding sites is activated and the activation can be detected. This system has made it practicable to identify and clone genes, the products of which interact with a known protein of special interest . The known protein is fused to Gal4p-BD and expressed in a gal4 deletion strain. Libraries of these fusions are screened for clones which activate a GAL4-regulated promoter.
The S. cerevisiaeSnf/Cat kinase is a homologue of the highly conserved AMP-activated serine/threonine kinases, which are found in plants, Drosophila, Caenorhabditis elegans, mammals and fungi (for review, see ). The Snf/Cat kinase contains a catalytic α-subunit encoded by SNF1, a regulatory γ subunit encoded by CAT3 (SNF4), and the β-subunits, which act as scaffold proteins, having structural rôles as temporary structural frameworks but no catalytic properties.
This interpretation of the genetic results of yeast two-hybrid analysis was recently confirmed biochemically, using ‘tandem-affinity-purification’ and MALDI–TOF–MS (mass spectrometry) to analyse the protein composition of protein complexes . The N-terminal glycine residue of Sip2 is modified by myristoylation .
Protein N-myristoylation promotes weak and reversible protein–membrane interactions .
Zinc cluster proteins: some regulators of transcription contain a zinc cluster (or zinc finger) which enables them to bind to specific DNA sequences. For example, X-ray crystallography has shown that Gal4p binds to certain DNA sequences, CGG N11 CCG, with each zinc cluster recognizing a CGG triplet. Many DNA-binding proteins have a zinc cluster, which is a polypeptide chain bound to a zinc atom.
Double control system: two systems, and if one fails the other one will take over.
D-fructose 2,6-bisphosphate was demonstrated in Saccharomyces cerevisiae in 1981 .
Helmut Holzer (1921–1997), German biochemist, was a pioneer in the study of enzyme regulation. When he was aged 18, World War II began, and he was obliged to undertake labour (Arbeitdienst) constructing fortifications along the Rhine. He was in the German army in France and then was wounded in Russia. Holzer joined Feodor Lynen's group at Munich in 1945 to work on the metabolism of butanol in yeast cells, moving to Hamburg in 1953 and thence to become professor of biochemistry at Freiburg-im-Breisgau in 1956 .
Several of these mechanisms, particularly induction, were considered in article number 7 of this series.
Coen P. M. Görts (b. 1935), Dutch microbial biochemist, worked in the Botanical Laboratory, State University, Utrecht, The Netherlands, from 1961 to 1972, when he moved to the education department. (C. P. M. Görts, personal communication).
Cycloheximide is often used as an inhibitor of protein synthesis, but it is reported to inhibit glycolysis markedly .
Proteases (or proteinases), a term originally used in 1928 by Wolfgang Grassmann (1898–1978) and Hanns Dyckerhoff (1904–1965) , are orthodoxly called ‘peptidases’ or ‘peptide hydrolases’; this term applies to any enzymes that hydrolyse peptide bonds .
Protease A was purified and described in 1980 ; originally designated EC 126.96.36.199, later 188.8.131.52, and named saccharopepsin, yeast endopeptidase A or Saccharomyces aspartic proteinase  .
These proteases are primarily translated as larger proteins from which the active proteases are matured after proteolytic cleavage.
This became clear after isolating mutants defective for (a) protease A (pep4) , (b) protease B (prb1)  , (c) carboxypeptidase Y (prc1) and (d) carboxypeptidase S (cps1); for review see   ; for activities of several proteases (protease A, protease B, and carboxypeptidase Y), see  .
Ubiquitin is a small protein (8.5 kDa) which attaches to proteins as a preliminary to their destruction in proteasomes. Ubiquitin has been described as ‘the cellular equivalent of the ‘black spot’ of Robert Louis Stevenson's Treasure Island: the signal for death’ [36, p. 635].
Proteasomes, which occur in the yeast cytoplasm and nucleus, are nanocompartments, where proteolysis is confined. The term was first used in 1988 for particles in HeLa cells , and described as very large peptidases with several non-identical subunits and, later, as 20 S cylindrical particles in various eukaryotes  . In order to move proteins to a proteasome, they are polyubiqutinylated by means of an enzyme cascade, consisting of an ubiquitin-activating enzyme, ubiquitin-conjugating enzymes and ubiquitin–protein ligases which mark these proteins for degradation   .
The gid mutants were analysed further by Michael Thumm, Dieter Wolf and their colleagues; see also .
EUROSCARF, the European SaccharomycescerevisiaeArchive for Functional Analysis, contains deletion mutants of all yeast genes (http://www.srd-biotec.de/euroscarf or http://web.uni-frankfurt.de/fb15/mikro/euroscarf/).