Coenzyme specificity conversion

T. Yaoi, K. Miyazaki, T. Oshima, Y. Komukai, and M. Go, Conversion of the coenzyme specificity of isodtrate dehydrogenase by module replacement, J. Biochem. (Tokyo) 1996, 119, 1014-1018. 

Although numerous enzymatic reactions requiring vitamin B12 have been described, and 10 reactions for adenosylcobalamin alone have been identified, only three pathways in man have so far been recognized, one of which has only recently been identified (PI). Two of these require the vitamin in the adenosyl form and the other in the methyl form. These cobalamin coenzymes are formed by a complex reaction sequence which results in the formation of a covalent carbon-cobalt bond between the cobalt nucleus of the vitamin and the methyl or 5 -deoxy-5 -adenosyl ligand, with resulting coenzyme specificity. Adenosylcobalamin is required in the conversion of methylmalonate to succinate (Fig. 2), while methylcobalamin is required by a B12-dependent methionine synthetase that enables the methyl group to be transferred from 5-methyltetrahydrofolate to homocysteine to form methionine (Fig. 3). 

Pharmacology These agents specifically competitively inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme which catalyzes the early rate-limiting step in cholesterol biosynthesis, conversion of HMG-CoA to mevalonate. 

The interconversion of these forms of foiic acid takes place through various electron transfer reactions facilitated by specific enzyme systems and coenzymes, such as the reduced forms of fiavin-adenine dinucleotide (FADH2) and NADPH. The conversion between the N -, N -methylene form and -formyl forms is readily reversible, but the reduction of methylene to methyl and reduction of free THF to formyltetrahydrofolate is essentially irreversible. Conversion of N -methyltetrahydrofolate back to free THF. may require cobalamin. 

Reaction inhibitors slow reaction rates. Nitrogen mineralization and nitrification (conversion of organic nitrogen and ammonium to nitrate) rates in soils, for example, can be slowed temporarily by chemicals that specifically slow or stop the microorganisms involved. Toxic metals can also operate as enzyme inhibitors, by replacing the metal coenzyme portion of an enzyme and thereby inactivating it. 

The aromatic hydroxylases or mixed-function oxidases are no exception to the above generalization. For maximum activity they require a transition metal ion and an electron donor such as one of the pyridine or flavin nucleotide coenzymes further, they probably utilize molecular oxygen as the source of the hydroxylic oxygen an example is the liver microsomal hydroxylating system (27). As yet there is no comprehensive explanation to cover the mode of action of these enzymes, for on the one hand there are the specific hydroxylases which catalyze such conversions as L-phenylalanine to L-tyrosine (26) or tryptophan to 5-hydroxytrypto-... 

Table VIII. Relative Specific Activities of Vitamin B12 Coenzyme, Residual Substrate, and Product During the Conversion of D-1,2-Propanediol-1 - H to Propionaldehyde-2- H...

In conclusion, in spite of the simplicity of the structure of the molecules, the exact role that ascorbic acid plays as a coenzyme remains unknown. The vitamin is suspected to influence reactions in numerous metabolic pathways (see Fig. 4-19), and it also interacts in some way with hormones. Whether the role of ascorbic acid is a specific one as a coenzyme or results from its potent reductive properties is not clear. In any case, the metabolic alteration which seems to be most closely related to the clinical manifestation of scurvy is the conversion of proline to hydroxyproline. 

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