Reinhard Jeck

Bio: Reinhard Jeck is an academic researcher from Goethe University Frankfurt. The author has contributed to research in topics: NAD+ kinase & Cofactor. The author has an hindex of 12, co-authored 35 publications receiving 386 citations.

Mitochondrial aldehyde dehydrogenase from horse liver: correlations of the same species variants for both the cytosolic and the mitochondrial forms of an enzyme

Abstract: The primary structure of the mitochondrial form of horse liver aldehyde dehydrogenase has been determined, utilizing peptide analyses and homology with other enzyme forms. The subunit exhibits N-terminal heterogeneity in size similar to that for the corresponding human mitochondrial protein, the longest form having 500 residues. Catalase was identified as a contaminant of the preparations. All four pairs within a set of aldehyde dehydrogenases can now be compared, including the same two species variants (horse and human) for both the cytosolic and mitochondrial enzyme, revealing characteristic differences although Cys-302 and other segments of presumed functional importance are unchanged. The cytosolic and mitochondrial enzymes are clearly different (172 exchanges in the horse pair; 160 exchanges in the human pair) and the mitochondrial forms are more conserved (28 exchanges of 500 residues) than the cytosolic ones (43 exchanges). Distributions of the residue substitutions also differ between the two enzyme types. These results suggest a comparatively distant separation of the cytosolic and mitochondrial enzymes into forms with separate functional constraints that are more strict on the mitochondrial than the cytosolic enzyme. Unexpectedly, positions with residues unique to one of the four enzymes are about twice as common in both of the horse proteins than in either of the human proteins. This difference may reflect a general pattern for human/non-human proteins, showing that not only functional properties of the protein, but also other factors, such as generation time (longer in man than in horse), are important for enzyme divergence.

Characterization of the coenzyme binding site of liver aldehyde dehydrogenase: differential reactivity of coenzyme analogues.

Abstract: The mitochondrial isozyme of horse liver aldehyde dehydrogenase was labeled with brominated [5-(3-acetylpyridinio)pentyl]diphosphoadenosine. Specific labeling of a coenzyme binding region was proven by an enzymatic activity of the isozyme with the nonbrominated coenzyme derivative, optical properties of the complex, stoichiometry of incorporation, and protection against inactivation. A cysteine residue was selectively modified by the brominated coenzyme analogue and was identified in a 35-residue tryptic peptide. This cysteine residue corresponds to Cys-302 of the cytoplasmic isozyme and has earlier been implicated in disulfiram binding, confirming a position close to the active site. In contrast, the butyl homologue of the coenzyme analogue labels another residue of the mitochondrial isozyme. Thus, in the same isozyme, two residues are selectively reactive. They are concluded to be close together in the tertiary structure and to be close enough to the coenzyme binding site to be differentially labeled by coenzyme analogues differing only by a single methylene group.

4 Lactate Dehydrogenase

Abstract: 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.

3 Alcohol Dehydrogenases

Abstract: Publisher Summary This chapter describes the advances with an emphasis on the structures of the alcohol dehydrogenases and the relationship between structure and function Yeast and mammalian alcohol dehydrogenase differ in substrate specificity and rate of catalytic activity The classic yeast enzyme is more specific for acetaldehyde and ethanol, which is consistent with its recognized physiological Significance to participate in alcohol fermentation at the end of the glycolytic pathway Enzyme forms with other functions and properties also occur in yeast The mammalian enzymes have broad substrate specificity and, even with primary alcohols, the maximum activity is not observed with ethanol Alcohols including ethanol, produced in the intestinal tracts mainly by bacterial actions, are found in the portal vein One physiological function of liver alcohol dehydrogenase may be to metabolize these products Structural studies have established that mammalian alcohol dehydrogenases have a distant evolutionary link to both the yeast and bacterial enzymes Ingested alcohol is metabolized to acetaldehyde mainly by the action of liver alcohol dehydrogenase

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

Abstract: Glucocorticoid action on target tissues is determined by the density of “nuclear” receptors and intracellular metabolism by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental “programming.” The role of 11β-HSD2 as a marker of programming is being explored. The 11β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.

Molecular Characterization of Microbial Alcohol Dehydrogenases

Abstract: There is an astonishing array of microbial alcohol oxidoreductases. They display a wide variety of substrate specificities and they fulfill several vital but quite different physiological functions. Some of these enzymes are involved in the production of alcoholic beverages and of industrial solvents, others are important in the production of vinegar, and still others participate in the degradation of naturally occurring and xenobiotic aromatic compounds as well as in the growth of bacteria and yeasts on methanol. They can be divided into three major categories. (1) The NAD- or NADP-dependent dehydrogenases. These can in turn be divided into the group I long-chain (approximately 350 amino acid residues) zinc-dependent enzymes such as alcohol dehydrogenases I, II, and III of Saccharomyces cerevisiae or the plasmid-encoded benzyl alcohol dehydrogenase of Pseudomonas putida; the group II short-chain (approximately 250 residues) zinc-independent enzymes such as ribitol dehydrogenase of Klebsiella aerogenes; the group III "iron-activated" enzymes that generally contain approximately 385 amino acid residues, such as alcohol dehydrogenase II of Zymomonas mobilis and alcohol dehydrogenase IV of Saccharomyces cerevisiae, but may contain almost 900 residues in the case of the multifunctional alcohol dehydrogenases of Escherichia coli and Clostridium acetobutylicum. The aldehyde/alcohol oxidoreductase of Amycolatopsis methanolica and the methanol dehydrogenases of A. methanolica and Mycobacterium gasti are 4-nitroso-N,N-dimethylaniline-dependent nicotinoproteins. (2) NAD(P)-independent enzymes that use pyrroloquinoline quinone, haem or cofactor F420 as cofactor, exemplified by methanol dehydrogenase of Paracoccus denitrificans, ethanol dehydrogenase of Acetobacter and Gluconobacter spp. and the alcohol dehydrogenases of certain archaebacteria. (3) Oxidases that catalyze an essentially irreversible oxidation of alcohols, such as methanol oxidase of Hansenula polymorpha and probably the veratryl alcohol oxidases of certain fungi involved in lignin degradation. This review deals mainly with those enzymes for which complete amino acid sequences are available. The discussion focuses on a comparison of their primary, secondary, tertiary, and quaternary structures and their catalytic mechanisms. The physiological roles of the enzymes and isoenzymes are also considered, as are their probable evolutionary relationships.

Aldehyde Dehydrogenases and Their Role in Carcinogenesis

Abstract: Aldehydes are highly reactive molecules that may have a variety of effects on biological systems. They can be generated from a virtually limitless number of endogenous and exogenous sources. Although some aldehyde-mediated effects such as vision are beneficial, many effects are deleterious, including cytotoxicity, mutagenicity, and carcinogenicity. A variety of enzymes have evolved to metabolize aldehydes to less reactive forms. Among the most effective pathways for aldehyde metabolism is their oxidation to carboxylic acids by aldehyde dehydrogenases (ALDHs). ALDHs are a family of NADP-dependent enzymes with common structural and functional features that catalyze the oxidation of a broad spectrum of aliphatic and aromatic aldehydes. Based on primary sequence analysis, three major classes of mammalian ALDHs--1, 2, and 3--have been identified. Classes 1 and 3 contain both constitutively expressed and inducible cytosolic forms. Class 2 consists of constitutive mitochondrial enzymes. Each class appears to oxidize a variety of substrates that may be derived either from endogenous sources such as amino acid, biogenic amine, or lipid metabolism or from exogenous sources, including aldehydes derived from xenobiotic metabolism. Changes in ALDH activity have been observed during experimental liver and urinary bladder carcinogenesis and in a number of human tumors, including some liver, colon, and mammary cancers. Changes in ALDH define at least one population of preneoplastic cells having a high probability of progressing to overt neoplasms. The most common change is the appearance of class 3 ALDH dehydrogenase activity in tumors arising in tissues that normally do not express this form. The changes in enzyme activity occur early in tumorigenesis and are the result of permanent changes in ALDH gene expression. This review discusses several aspects of ALDH expression during carcinogenesis. A brief introduction examines the variety of sources of aldehydes. This is followed by a discussion of the mammalian ALDHs. Because the ALDHs are a relatively understudied family of enzymes, this section presents what is currently known about the general structural and functional properties of the enzymes and the interrelationships of the various forms. The remainder of the review discusses various aspects of the ALDHs in relation to tumorigenesis. The expression of ALDH during experimental carcinogenesis and what is known about the molecular mechanisms underlying those changes are discussed. This is followed by an extended discussion of the potential roles for ALDH in tumorigenesis. The role of ALDH in the metabolism of cyclophosphamidelike chemotherapeutic agents is described. This work suggests that modulation of ALDH activity may an important determinant of the effectiveness of certain chemotherapeutic agents.(ABSTRACT TRUNCATED AT 400 WORDS)