Homocysteine sulfur oxidation

A. DIRECT OXIDATION OF THE SULFUR OF HOMOCYSTEINE 1. Oxidation of Homocysteine to Homocystine and the Fate of Homocystine... 

There are two reports describing the preparation of derivatives of 1,2-thiazetidine-1,1-dioxide. The sulfur atom in L-cystine diethyl ester was oxidized and the corresponding sulfonyl chloride was cyclized with ammonia (Scheme 3) (60CB784). A similar transformation used protected )3-homocysteine as starting material (94LA251). 

Tetrahydrofolate, a carrier of activated one-carbon units, plays an important role in the metabolism of amino acids and nucleotides. This coenzyme carries one-carbon units at three oxidation states, which are interconvertible most reduced—methyl intermediate—methylene and most oxidized—formyl, formimino, and methenyl. The major donor of activated methyl groups is -adenosylmethionine, which is synthesized by the transfer of an adenosyl group from ATP to the sulfur atom of methionine. -Adenosylhomocysteine is formed when the activated methyl group is transferred to an acceptor. It is hydrolyzed to adenosine and homocysteine, the latter of which is then methylated to methionine to complete the activated methyl cycle. 

Methionine is converted to iS-adenosylmethionine (SAM), which donates its methyl group to other compounds to form S-adenosylhomocysteine (SAH). SAH is then converted to homocysteine (Fig. 39.14). Methionine can be regenerated from homocysteine by a reaction requiring both FH4 and vitamin B12 (a topic that is considered in more detail in Chapter 40). Alternatively, by reactions requiring PLP, homocysteine can provide the sulfur required for the synthesis of cysteine (see Fig. 39.7). Carbons of homocysteine are then metabolized to a-ketobutyrate, which undergoes oxidative decarboxylation to propionyl-CoA. The propionyl-CoA is then converted to snccinyl CoA (see Fig. 39.14). 

MetH catalyzes the methylation of the bound and reduced cob(I)alamin cofactor by (N -protonated) N -methyltetrahydrofolate to give enzyme-bound methylcobalamin (3) in a base-off/His-on form (see later) [125,153-155]. The methyl-Co(III)corrinoid is demethylated by homocysteine, whose sulfur is activated and deprotonated due to the coordination to a zinc ion (held by three cysteine residues) of the homocysteine binding domain [164] (see Fig. 15). The two methyl-transfer reactions occur in a sequential mechanism [124,125,153,154]. Intermittently, the bound Cob(I)alamin (40 ) is oxidized to enzymatically inactive cob(II)alamin (23) and requires reactivation by reductive methylation with SAM and a flavodoxin as a reducing agent [125,153-155,165]. 

Vitamin B12 is an essential coenzyme for the methylation cycle by activating THF. An activated folate is not only a coenzyme for methionine synthase but also plays a pivotal role in one-carbon metabolism it promotes the generation of methionine from homocysteine, which is a cytotoxic sulfur-containing amino acid that can induce DNA strand breakage, oxidative stress and apoptosis. The methylation cycle is very important in the brain and depends on the SAM concentration. 

Synthesis of Sulfur Amino Acids. Of the many oxidation states of sulfur, only sulfite has been shown to be utilized by cell-free systems in the net synthesis of compounds with carbon-sulfur bonds, although mutant studies have indicated that more reduced forms can be incorporated. The formation of cysteinesulfinic acid from sulfite has been demonstrated in extracts of acetone-dried rabbit kidney it is possible that this reaction participates in the principal mechanism of sulfur incorporation. In many organisms that require preformed sulfur amino acids, cysteine may be formed from methionine. Only the sulfur of methionine is transferred to cysteine the carbon skeleton of cysteine is derived exclusively from serine. Transsulfuration appears to require the formation of homocysteine from methionine. Homocysteine and serine condense to form a thioether, cystathionine (V). Pyridoxal phosphate has been... 

The formation of homocysteine from methionine is thus an established fact. This homocysteine, in animals, and particularly in dogs, imder-goes a series of reactions, resulting in the oxidation of its sulfur and excretion of the latter in the form of sulfate or taurine (136). We are thus led to the study of the mechanisms of this oxidation. 

In analogy with what is known about the oxidation of cysteine to cystine, one can admit the possibility of the oxidation of homocysteine to homocystine, imder certain conditions, although no exact study of such an oxidation by a biological path seems to have been carried out as yet. It is of interest to compare homocysteine metabolism with that of homocystine. In comparing these two, one notes very distinct differences in the metabolism. The work of Virtue and Doster-Virtue (134) shows that the sulfur of homocystine ingested by dogs is excreted mainly in the form of... 

---