Alcohol dehydrogenase liver, inhibitors

Some of the most important aromatic pyrazoles with biological activity are shown in Table 38. Pyrazole itself and several A-unsubstituted pyrazoles are inhibitors and deactivators of liver alcohol dehydrogenase (79JMC356, 79ACS(B)483, B-79MI40414, 82ACS(B)10l). 

Figure 17.8 Catal3ftic zinc center of horse liver alcohol dehydrogenase revealed from an X-ray crystallographic structure (PDB file 20HX) [Al-Karadaghi et al., 1994]. The bound NADH cofactor, a molecule of the inhibitor dimethylsulfoxide (DMSO), and the amino acid residues that coordinate the Zn are shown as sticks shaded according to the elements, and the Zn center is shown as a gray sphere, while the protein is shown in thin gray lines.

The enzyme chemistry of cyclopropylmethanols has been studied both as inhibitors and mechanistic probes [4, 47]. Thus, a series of alkylcyclopropyl-methanol derivatives have been proved as being inhibitors of horse liver alcohol dehydrogenase. There are two sites in the cyclopropylmethanol inhibitors able of reacting with nucleophiles ... 

A potent five-membered heterocyclic inhibitor (the chemical systematic name is 1,2-diazole) that strongly inhibits liver alcohol dehydrogenase. See Alcohol Dehydrogenase... 

Uncompetitive inilibitors of liver alcohol dehydrogenase (Chapter 15) could be used to treat cases of poisoning by methanol or ethylene glycol.81 83 The aim is to prevent rapid oxidation to the toxic acids HCOOH and HOCH2COOH, which lower blood pH, while the alcohols are excreted. Uncompetitive inhibitors have an advantage over competitive inhibitors as therapeutic agents in that the inhibition is not overcome when the substrate concentration is saturating.84... 

A crystal structure of a ternary complex of horse liver alcohol dehydrogenase with NADH and the inhibitor, dimethyl sulfoxide, first at 4.5 A resolution1365 and a further refinement to 2.9 A resolution,1366 has been published by Eklund et al. The gross structure of the ternary complex is similar to that of the free enzyme structure. Each subunit is divided into a coenzyme-binding domain and a catalytic domain. The subunits are joined together near the... 

N-1 ormy [piperidine (4.15) is an uncompetitive inhibitor of liver alcohol dehydrogenase (Figure 4.18).14 Liver alcohol dehydrogenase is often associated with the oxidation of ethanol in the bloodstream, but it also oxidizes methanol to formaldehyde, which is a toxic metabolite. Safe, effective inhibitors of liver alcohol dehydrogenase represent a potential treatment for individuals who have ingested methanol. 

The initial rates (v in juM/min) of liver alcohol dehydrogenase-catalyzed ethanal reduction are measured in the presence of pyrazole as an inhibitor at the constant concentration of NADH (0.02 M) and the constant concentration of ethanal (2.0 mM), respectively. Propose respective inhibition types and estimate their inhibition constants. 

Figure 2. SDS gel electrophoresis of the products of partial cystine cleavage for several test proteins. A. molecular weight standards, B. yeast alcohol dehydrogenase. C. P-lactoglobulin, D. hen egg lysozyme, E. ovalbumin, F. calf fetal serum fetuin. Molecular weight standards are indicated by arrows on the left side of the gel and are bovine serum albumin (66,300), bovine liver glutamate dehydrogenase (55,400), porcine muscle lactate ddiydiogenase (36,500), bovine erythrocyte carbonic anhydrase (31,000), soybean trypsin inhibitor (21,500), hen egg lysozyme (14,400), bovine lung aprotinin (6,000), unresolved bovine pancreatic insulin A and B chains.

Pavelka and Kov f studied 24 derivatives of protoberberine for their interaction with liver alcohol dehydrogenase. The inhibitory power of the tested compounds was correlated with their structures and with some properties following from those structures. The most effective inhibitor of liver alcohol dehydrogenase is 13-ethylberberine, which is bound more firmly to the enzyme at pH 10 than NAD and NADH (670). 

Some of Al Martini s problems have arisen from product inhibition of liver alcohol dehydrogenase by NADH. As ethanol is oxidized in liver cells, NAD+ is reduced to NADH and the NADH/NAD+ ratio rises. NADH is an inhibitor of alcohol dehydrogenase, competitive with respect to NAD, so the increased NADH/NAD+ ratio slows the rate of ethanol oxidation and ethanol clearance from the blood. 

The interaction between alcohol and vitamin A is complex. They have overlapping metabolic pathways a similar 2-step process is involved in the metabolism of both alcohol and vitamin A, with alcohol dehydrogenases and acetaldehyde dehydrogenases being implicated in the conversion of vitamin A to retinoic acid. Alcohol appears to act as a competitive inhibitor of vitamin A oxidation. In addition, chronic alcohol intake can induce cytochrome P450 isoenzymes that appear to increase the breakdown of vitamin A (retinol and retinoic acid) into more polar metabolites in the liver, which can cause hepatocyte death. So chronic alcohol consumption may enhance the intrinsic hepatotoxicity of high-dose vitamin A. Alcohol has also been shown to alter retinoid homoeostasis by increasing vitamin A mobilisation from the liver to extrahepatic tissues, which could result in depletion of hepatic stores of vitamin A. ... 

The use of X-ray techniques to elucidate the three-dimensional structure of enzymes shows that many of them possess a characteristic concave cleft at the active site. Concavities of this type have been observed, for example, in the case of lysozyme [8, 9] trypsin [10], yeast hexokinase [11], liver alcohol dehydrogenase [12] and citrate synthase [13]. It is thus reasonable to assume that the interaction between an enzyme and its substrate, inhibitor or cofactor usually occurs not in bulk water but rather in a shielded proteic cleft whose specific microenvironment is induced by the amino acid residues forming the cleft. Hydrophobicity, electrostatics, solvation and a relatively low dielectric constant prevailing within the cleft no doubt play a decisive role in determining the nature and rate of the reaction catalyzed by the enzyme. 

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