Publisher Summary This chapter discusses the lactate dehydrogenase. Lactic acid is the end product of anaerobic glycolysis in muscle tissue has been known for all of this century. Cell-free extracts able to catalyze the oxidation of lactate to pyruvate. The five different permutations of two different polypeptide chains readily explained the electrophoretic patterns. The distribution of these two polypeptide chains was dependent on whether the extract originated in aerobic tissue, such as heart or in anaerobic tissue as in skeletal muscle. The NAD + binding structure found in L-lactate dehydrogenase (LDH) occurs frequently in other dehydrogenases and other proteins. In LDH the problem of catalysis is presented in stark simplicity. The complications of metal ions, linked substrate phosphorylation, or of ammonia uptake are absent. LDH is the only simpler dehydrogenase where both structure and sequence are known at present. The concept of multiple molecular forms of LDH has stimulated many investigations into the nature, function, and control of isozymes. There are only two major structural genes and there is a complex variety of other LDH genes, which can be expressed in some tissues at certain stages of development.

4 Lactate Dehydrogenase

https://science.sciencemag.org/content/sci/143/3609/929.full.pdf

Lactic Dehydrogenases: Functions of the Two Types

Publisher Summary This chapter discusses the important roles of glutamate and gamma-aminobutyric acid (GABA) in brain metabolism. The chapter shows the amino acids as excitatory and inhibitory transmitters in the CNS. The inactivation of these transmitters is generally brought about by sodium-dependent high-affinity uptake systems rather than enrymatic degradation. The importance of the different cell types in these processes and the characteristics of the different transport systems are discussed. The quantitative importance of the high-affinity uptake of glutamate and GABA into glial cells is investigated in primary cultures of astrocytes that seem to constitute a valid model for such cells in vivo. From these studies, it can be concluded that astrocytes are quantitatively important for uptake of putative transmitter amino acids. Whether this uptake has to do primarily with the transmitter pools of these amino acids, and hence their inactivation, or the uptake is involved in the metabolic processes remains to be finally elucidated. The fact that the processes of astrocytes control a large surface area around synapses seems to favor a function of such cells in the inactivation of these amino acids.On the other hand, it is undoubtedly correct that these amino acids can be taken up into presynaptic nerve endings through high-affinity transport processes. In the case of GABA, it is even possible to distinguish between these transport mechanisms employing inhibitors that have been shown to be selective for the transport carriers.

Transport and metabolism of glutamate and GABA in neurons are glial cells.

Ann. H u m . Genet., Lond. (1971), 34, 251 Printed in Great Britain Developmental changes and polymorphism in human alcohol dehydrogenase BY MOYRA SMITH, D. A. HOPKINSON AND HARRY HARRIS M.R.C. Human Biochemical Genetics Unit, Galton Laboratory, University College London I n man, alcohol dehydrogenase (alcohol: NAD oxidoreductase E.C. 1 . 1 . 1 . 1 ) occurs princi- pally in liver, though low levels of activity have aIso been found in lung, kidney and the gastro- intestinal tract (Moser, Papenberg & von Wartburg, 1968). Evidence for at least three distinct isozymes has been obtained by chromatography of liver extracts on CM cellulose (Blair & Vallee, 1966) and also by electrophoresis (Moser et al. 1968; Pikkarainen & Raiha, 1969; Murray & Motulsky, 1970). Von Wartburg, Papenberg & Aebi (1965) reported that certain individuals have an atypical form of alcohol dehydrogenase associated with an increased level of activity. The usual and atypical forms of the enzyme were shown to differ markedly in pH activity curves with ethanol as substrate. The pH optimum for the usual form was found to be pH 10.8 and for the atypical form pH 8.5. The enzymes also differed in the relative rates at which they oxidized various other alcohols, and in the degree of inhibition produced by various metal binding agents. On the other hand no significant differences were observed in Michaelis constants for the substrates ethanol or acetaldehyde or for the corresponding coenzymes NAD or NADH. Also the pH activity curve with acetaldehyde as substrate was essentially the same for both enzymes, having an optimum at pH 6.0-6.5. A simple screening test to distinguish the usual from the atypical enzyme in crude liver homo- genates was designed (von Wartburg et al. 1965). This involves determining the ratio of the activity at pH 11.0 to that at pH 8-8 with ethanol as substrate under standard conditions. The usual enzyme gives a value for this ratio greater than 1.0, and the atypical enzyme less than 1.0. In a survey of 59 liver samples from different individuals in Switzerland, 12 were found to have the atypical alcohol dehydrogenase, and in another series of 50 individuals from London, 2 were found to be atypical (von Wartburg & Schiirch, 1968). The atypical enzyme occurred in indi- viduals varying from 16 to 82 years of age. Pikkarainen & Raiha (1967) reported that alcohol dehydrogenase activity in liver is low during foetal life and reaches adult levels about 5 years after birth. Changes in electrophoretic pattern have also been noted during development (Pikkarainen & Raiha, 1969; Murray & Motulsky, 1970). In the earliest stages only a single isozyme is observed but later further iso- zymes appear. I n adult liver individual variations in the relative contribution of the different isozymes to the total activity have been noted (von Wartburg & Schiirch, 1968), but no clear electrophoretic differences between the usual and atypical alcohol dehydrogenases as determined by the ratio of activity at pH 11.0 and pH 8.8 were detected. The present paper is concerned with a study of human alcohol dehydrogenase in which liver, lung, kidney and intestinal material from foetuses, infants and adults has been examined. The en- zyme has been investigated both by spectrophotometric assay at different pH’s and by starch-gel

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Developmental changes and polymorphism in human alcohol dehydrogenase

Summary A definite and consistent shift in the pattern of molecular forms of lactic dehydrogenase (LDH) has been found in a large series of malignant human neoplasms as compared with benign tumors and normal controls. This has been associated in most cases with an absolute increase in the muscle-type LDH (migrating negatively on electrophoresis). No correlation was found between the degree of these changes and the histologic grading of the tumors. Suggestive but not conclusive evidence was found for an increase in total LDH activity in malignant tumors. In contrast, metastatic nodules were shown to have lower enzyme activity levels and different LDH compositions when compared with their associated primary tumors. The benign tumors were essentially indistinguishable from their normal tissue of origin. The significance of these findings in relation to the known characteristic increase of glycolytic activity in malignant neoplasms is discussed. Consideration is also given to the possible implications of these results for carcinogenesis and cancer chemotherapy.

https://cancerres.aacrjournals.org/content/canres/24/3_Part_1/389.full.pdf

N. O. Kaplan

Papers

Developmental Changes of Mammalian Lactic Dehydrogenases

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