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Correction
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Welch and Loscalzo,
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-synthase is in the wrong step of the proposed pathway, and the enzyme cystathioninase is not included at all.
The structure of homocysteine is missing one carbon in its backbone. Homocysteine is a four-carbon species, whereas the figure depicts it as a three-carbon species (the actual molecule depicted is therefore cysteine, not homocysteine). The structure of glutathione is also missing a carbon; what should be the 
carbon on the glutamic acid residue has a carbonyl group instead of the correct carboxylic acid functional group.2
In addition, the reaction catalyzed by cystathionine -synthase is the formation of cystathionine from serine and homocysteine, and thus, cystathionine -synthase is in the wrong location along the reaction pathway. Cystathioninase then catalyzes the cleavage of cystathionine into homoserine (which is subsequently metabolized to -ketobutyrate) and cysteine.2
Matthew F. Lawson
Harvard University
Cambridge, MA 02138
References
First, the metabolism of homocysteine as depicted in Figure 1 is not complete, given that in humans, there is an alternative biochemical pathway in which homocysteine can be remethylated back to methionine. This reaction, catalyzed by betaine–homocysteine S-methyltransferase, requires betaine as the methyl donor and no cofactor. Plasma total homocysteine has successfully been lowered by oral betaine supplementation, not only in patients with pyridoxine-resistant homocystinuria,1 but also in patients with a defect in cobalamin metabolism or with N5,N10-methylenetetrahydrofolate reductase deficiency,1,2 a disease for which Welch and Loscalzo state there is no therapy. We have treated patients who are undergoing hemodialysis with betaine in conjunction with folic acid, but we found no significant difference in the extent of plasma homocysteine reduction between this treatment and treatment with folic acid alone.3
Second, the authors suggest that reduced urinary excretion of homocysteine may be responsible for hyperhomocysteinemia in renal failure. In healthy persons, however, urinary excretion of homocysteine is negligible.4 In addition, we have recently demonstrated, using the renal arteriovenous-difference technique, that no net renal homocysteine metabolism occurs in subjects with normal renal function.5 Since, until now, high-dose multivitamin therapies have not been able to normalize plasma homocysteine levels in patients who are undergoing hemodialysis, future research on the cause and treatment of hyperhomocysteinemia in end-stage renal disease should therefore focus on extrarenal impairment of homocysteine metabolism.
Coen van Guldener, M.D.
Ab J.M. Donker, M.D., Ph.D.
Coen D.A. Stehouwer, M.D., Ph.D.
Free University Hospital
1007 MB Amsterdam, the Netherlands
References
Even after successful renal transplantation, the specter of hyperhomocysteinemia and increased cardiovascular mortality remains, and the former may reflect in part subclinical vitamin deficiencies and the use of immunosuppressive drugs such as cyclosporine. However, since plasma homocysteine concentrations increase with even mild renal insufficiency, a solitary, otherwise adequately functioning renal allograft may not sufficiently metabolize homocysteine. Increased intake of relevant vitamins may reduce hyperhomocysteinemia in patients with chronic renal insufficiency and renal-transplant recipients.1 It would be of interest, especially from a therapeutic standpoint, to identify the extent to which up-regulation of renal homocysteine-metabolizing pathways in a diminished complement of functioning nephrons can be induced by nutritional or other interventions.
Karl A. Nath, M.B., Ch.B.
Mayo Clinic
Rochester, MN 55905
References
To the Editor: We agree with the comments of Mr. Lawson and regret the errors in the figure. With regard to the comments of Dr. van Guldener and colleagues and Dr. Nath on homocysteine and renal disease, we appreciate their views of recent insights into renal metabolism and therapeutic options and believe they complement and enhance the information provided in the review.
George N. Welch, M.D.
Joseph Loscalzo, M.D., Ph.D.
Boston University School of Medicine
Boston, MA 02118
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