Metabolic consequences of hyperhomocysteinemia in uremia.
An elevated blood level of homocysteine (Hcy), a sulfur amino acid, is associated with increased cardiovascular risk. Hcy is generated from S-adenosylhomocysteine (AdoHcy), the demethylated product of S-adenosylmethionine (AdoMet) in transmethylation reactions. AdoHcy is a competitive inhibitor of AdoMet-dependent methyltransferases. AdoHcy accumulation is prevented by rapid metabolism of its products. Chronic renal failure (CRF) is almost constantly associated with hyperhomocysteinemia. It has been shown that: (1) AdoHcy concentration is significantly increased and the AdoMet-AdoHcy ratio is reduced in erythrocytes of patients with CRF; (2) erythrocyte membrane protein 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 (detrimental to protein structure and function) into a normal peptide bond; (3) D-aspartate residues, a side product of protein methylation and repair, are significantly reduced in erythrocyte membrane proteins of patients with CRF; and (4) folate treatment significantly reduces plasma Hcy levels and improves AdoMet-AdoHcy ratios. Stable isotope studies recently confirmed that the rate of methyl transfer reactions is significantly reduced in uremia. Additional evidence, obtained by independent groups, is consistent with this interpretation. We recently found increased isoaspartyl content of circulating plasma protein levels, particularly albumin, which was only partially reduced after folate treatment, in uremia. This kind of molecular damage possibly is caused by protein increased intrinsic instability as a result of interference with the uremic milieu. In conclusion, Hcy is an uremic toxin involved in protein molecular damage through the inhibition of methylation reactions and protein PCMT-mediated repair.
Perna
A F
AF
Department of Pediatrics, Division of Nephrology, and Department of Biochemistry and Biophysics, School of Medicine, Second University of Naples, Naples, Italy. alessandra.perna@unina2.it
Ingrosso
D
D
Satta
E
E
Romano
M
M
Cimmino
A
A
Galletti
P
P
Zappia
V
V
De Santo
N G
NG
D002318:Cardiovascular Diseases / Q000209:etiology / Q000517:prevention & control; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D020138:Hyperhomocysteinemia / Q000209:etiology / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000150:complications / Q000378:metabolism* / Q000628:therapy; D008297:Male; D008745:Methylation; D006435:Renal Dialysis; D012307:Risk Factors; D012737:Sex Factors; D014511:Uremia / Q000150:complications / Q000378:metabolism; D014805:Vitamin B 12 / Q000378:metabolism; D025101:Vitamin B 6 / Q000378:metabolism
D025101:Vitamin B 6; D014805:Vitamin B 12