Dehydrogenases, structure-activity

The Protein Data Bank PDB ID 1A71 Colby T D Bahnson B J Chin J K Klinman J P Goldstein B M Active Site Modifications m a Double Mutant of Liver Alcohol Dehydrogenase Structural Studies of Two Enzyme Ligand Com plexes To be published... 

Hansch, C. et al. (1986) A quantitative structure-activity relationship and molecular graphics analysis of hydrophobic effects in the interactions of inhibitors with alcohol dehydrogenase. J. Med. Chem., 29 (5), 615-620. 

The problem of biomimetic model design simulating the action mechanism of corresponding enzymes is based on the idea of structural-functional conformity. In 1971, alcohol dehydrogenase was primarily synthesized [123], In this biomimetic system the product is formed due to direct electron transfer from the reduced co-factor (NADH) analog to aldehyde. Note that the display of alcohol dehydrogenase catalytic activity requires the presence of zinc (II) ion. 

X-Ray data are also useful for molecular modeling of the biological potency. Thus, the X-ray data of benzazocine 12 were manipulated in connection with its inhibitory effect on 17/3-hydroxysteroid dehydrogenase type 3 to support structure-activity relationship considerations <2006BML1532>. 

Figure 16.7. Structure of Glyceraldehyde 3-Phosphate Dehydrogenase. The active site includes a cysteine residue and a histidine residue adjacent to a hound NAD+. 

Active site modifications in a double mutant of liver alcohol dehydrogenase structural studies of two enzyme-ligand complexes. Biochemistry 37, 9295-9304. 

Several studies on structure-activity relationships of succinate dehydrogenase inhibitors have been published [22-28]. Each of the analyses has focused on specific carboxylic acid moieties of the molecule. The influence of substituents of the carboxylic acid and of the aniline has then been studied based on enzyme inhibition and biological data. Some empirical relationships have been established within each structural subclass. The importance of electron-withdrawing groups on the carboxylic acid and of lipophilic effects on the aniline has been observed. The orientation of the amide bond has also been discussed, suggesting that the cis configuration of the amide bond may be important in molecules with bulky ortho substituents [28]. 

Figure 4.17 Schematic structures for the active site of carbon monoxide dehydrogenase. Structure a shows that initially proposed from protein crystallography and h shows the final structure, based on improved crystallography and XAS.

REGULATION OF NADP-MALATE DEHYDROGENASE LIGHT-ACTIVATION BY THE REDUCING POWER H. STRUCTURAL STUDIES. 

C. Hansch, T. Klein, J. McClarin, R. Langridge, and N. W. Cornell, ]. Med. Chem., 29, 615 (1986). A Quantitative Structure-Activity Relationship and Molecular Graphics Analysis of Hydrophobic Effects in the Interactions of Inhibitors of Alcohol Dehydrogenase. 

Ren S, Wu S, Lien E (1998) Dihydroorotate dehydrogenase inhibitors quantitative structure-activity relationship analysis. Pharm Res 15 286-295... 

Peng H, Wang T, Xie P et al (2007) Molecular docking and three-dimensional quantitative structure-activity relationship studies on the binding modes of herbicidal l-(substituted phenoxyacetoxy) alkylphosphonates to the El component of pyruvate dehydrogenase. J Agric Food Chem 55 1871-1880... 

Oxidation of P-nicotinamide adenine dinucleotide (NADH) to NAD+ has attracted much interest from the viewpoint of its role in biosensors reactions. It has been reported that several quinone derivatives and polymerized redox dyes, such as phenoxazine and phenothiazine derivatives, possess catalytic activities for the oxidation of NADH and have been used for dehydrogenase biosensors development [1, 2]. Flavins (contain in chemical structure isoalloxazine ring) are the prosthetic groups responsible for NAD+/NADH conversion in the active sites of some dehydrogenase enzymes. Upon the electropolymerization of flavin derivatives, the effective catalysts of NAD+/NADH regeneration, which mimic the NADH-dehydrogenase activity, would be synthesized [3]. 

The enzyme succinate dehydrogenase (SDH) is competitively inhibited by malo-nate. Figure 14.14 shows the structures of succinate and malonate. The structural similarity between them is obvious and is the basis of malonate s ability to mimic succinate and bind at the active site of SDH. However, unlike succinate, which is oxidized by SDH to form fumarate, malonate cannot lose two hydrogens consequently, it is unreactive. 

FIGURE 20,20 (a) The structure of malate dehydrogenase, (b) The active site of malate dehydrogenase. Malate is shown in red NAD" is blue. 

Uncovering of the three dimentional structure of catalytic groups at the active site of an enzyme allows to theorize the catalytic mechanism, and the theory accelerates the designing of model systems. Examples of such enzymes are zinc ion containing carboxypeptidase A 1-5) and carbonic anhydrase6-11. There are many other zinc enzymes with a variety of catalytic functions. For example, alcohol dehydrogenase is also a zinc enzyme and the subject of intensive model studies. However, the topics of this review will be confined to the model studies of the former hydrolytic metallo-enzymes. 

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