Metabolic consequences of hyperhomocysteinemia in uremia

An elevated blood level of homocysteine (Hcy), a sulfur amino acid, is asso ciated with increased cardiovascular risk. Hcy is generated from S-adenosyl homocysteine (AdoHcy), the demethylated product of S-adenosylmethionine (Ad oMet) in transmethylation reactions. AdoHcy is a competitive inhibitor of A doMet-dependent methyltransferases. AdoHcy accumulation is prevented by rap id metabolism of its products. Chronic renal failure (CRF) is almost consta ntly associated with hyperhomocysteinemia. It has been shown that: (1) AdoH cy concentration is significantly increased and the AdoMet-AdoHcy ratio is reduced in erythrocytes of patients with CRF; (2) erythrocyte membrane prot ein methyl esterification, catalyzed by the enzyme protein L-isoaspartyl O- methyltransferase (PCMT; EC 2.1.1.77), is reduced in CRF; PCMT catalyzes a repair reaction involved in the conversion of an isopeptide bond (detriment al to protein structure and function) into a normal peptide bond; (3) D-asp artate residues, a side product of protein methylation and repair, are sign ificantly reduced in erythrocyte membrane proteins of patients with CRF; an d (4) folate treatment significantly reduces plasma Hcy levels and improves AdoMet-AdoHcy ratios. Stable isotope studies recently confirmed that the r ate of methyl transfer reactions is significantly reduced in uremia. Additi onal evidence, obtained by independent groups, is consistent with this inte rpretation. We recently found increased isoaspartyl content of circulating plasma protein levels, particularly albumin, which was only partially reduc ed after folate treatment, in uremia. This kind of molecular damage possibl y is caused by protein increased Intrinsic Instability as a result of inter ference with the uremic milieu. In conclusion, Hcy is an uremic toxin invol ved in protein molecular damage through the inhibition of methylation react ions and protein PCMT-mediated repair. (C) 2001 by the National Kidney Foun dation, Inc.