Homocysteine and chronic kidney disease: an ongoing narrative
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The cross-sectional study by Cohen et al.  conveys a wealth of information in a very large cohort of subjects (n = 17,010) on the homocysteine issue . Patients were referred for screening by their employers, and were 67% men. Israel is a country, like China, where no folic acid fortification is implemented. The association between homocysteine concentrations and CKD was looked upon and is confirmed at all levels of renal disease, while also adjusting for confounders which can affect CKD, such as age, smoking status, body mass index, hypertension and diabetes mellitus. The association is present in both men and women. Subjects with homocysteine > 15 μM were more likely to have an eGFR < 60 ml/min, and to have proteinuria. At a GFR < 60 ml/min, homocysteine was progressively higher in stages 3a, 3b, and 4 of CKD, with quite a large discrepancy between stage 3a and 3b, particularly in women. This could be of interest, given the fact that stage 3b is the one were cardiovascular disease hits the most, and it is therefore most likely to benefit from low-dose folic acid.
This is the first study carried out in such an elevated number of patients, outside China, in a country with no folate fortification policy. While it does not prove cause and effect relationships (homocysteine and CKD, homocysteine and CKD progression, homocysteine and atherosclerosis, etc.), Spence et al. have shown for example that homocysteine accounts for a significant part of the effect of renal impairment on atherosclerosis . This paper by Cohen et al. therefore paves the way for future studies on this topic.
A detailed scheme of the metabolic interconnections of homocysteine with sulfur amino acids, folate cycle, B vitamins, and one carbon (C1) metabolism is provided in Fig. 1. Methionine is converted into S-adenosylmetionine (SAM; AdoMet), the universal methyl donor for several tens of SAM-dependent methyltransferases (MTs) in humans. Methyl acceptors include small molecules (guanidino acetate, phospholipids, amino acids and their derivatives, etc.) and macromolecules. The demethylated product of SAM-dependent MTs is S-adenosylhomocysteine (SAH; AdoHcy), a thioether which is also a powerful competitive product inhibitor of all SAM-dependent MTs. SAH hydrolysis is catalyzed by SAH hydrolase (EC 220.127.116.11). Although thermodynamics favors SAH biosynthesis over hydrolysis, the prompt removal of hydrolysis products (homocysteine and adenosine) prevents SAH intracellular accumulation and the relevant MTs inhibition. Homocysteine concentration crucially depends on the rate of its formation (transmethylations), as well as on the rate of homocysteine removal. Homocysteine is mostly carried out in circulation covalently bound to serum albumin, thus preventing its excretion as such. Decreased metabolic clearance, possibly due to the effect of another uremic toxin , rather than increased production, supports the mechanism of onset of hyperhomocysteinemia in CKD. On a quantitative basis, small molecule methylation is more prominent than macromolecule methylation (DNA, RNA, proteins) in determining homocysteine production.
Homocysteine can be remethylated to methionine. Two enzymes are capable of catalyzing this reaction: the first (methionine synthase, MS; EC 18.104.22.168), the product of MTR gene, is vitamin B12-dependent and utilizes methyl tetrahydrofolate (methyl-THF) as the methyl donor. The other one (BHMT; EC 22.214.171.124) uses betaine as the methyl donor. Methyl-THF is generated from methylene-THF in a previous reaction catalyzed by methylene-THF reductase (MTHFR; E.C.126.96.36.199). The homocysteine remethylation lays at a crucial intersection between the methionine-homocysteine and the folate cycle. Vitamin B12, in the form of methylcobalamin linked to the MS apoenzyme, is required for this reaction, as well as SAM itself. The active B12 coenzyme is regenerated by the action of methionine synthase reductase (MTR; EC 188.8.131.52) the product of MTRR gene, a NADP+-dependent oxidoreductase; MTR is a flavoprotein containing FAD and FMN. The substrate of the enzyme is the inactive form of MS. Defects in these enzymes lead to hereditary hyperhomocysteinemia. Folate coenzymes are involved in the biosynthesis of both purine (formyl-THF) and dTMP biosynthesis, as crucial building blocks in DNA biosynthesis. TS (Thymidylate synthase; EC 184.108.40.206) oxidizes tetrahydrofolate (THF) to dihydrofolate (DHF). The latter must be reduced by the action of DHF-reductase (DHFR; EC 220.127.116.11), a NADPH-dependent oxidoreductase, which is the in vivo molecular target of the antifolic methotrexate (not shown).
Alternatively, homocysteine can be transsulfurated to cysteine, in a two-step, pyridoxal phosphate (PLP)-dependent pathway; this pathway depends on a key supply of B6, the PLP precursor. The transsulfuration rate-limiting reaction is catalyzed by cystathionine-β-synthase (CBS; EC 18.104.22.168), which catalyzes the condensation of serine with homocysteine, thus yielding cystathionine, a non-protein amino acid intermediate. Cystathionine is, in turn, hydrolyzed to α-ketobutyrate and cysteine by cystathionine-γ-lyase (cystathionase; CSE; EC 22.214.171.124). Cysteine is important for its role as a substrate for glutathione (GSH) biosynthesis. Both CBS or CSE are also bi-functional enzymes, in that they can independently use cysteine to synthesize hydrogen sulfide (H2S; evidenced by a star), the third gaseous vasodilator, after nitric oxide and carbon monoxide, thus yielding lanthionine as a side product. Lanthionine is regarded as a novel uremic toxin . Dashed circle indicates inhibition. All enzymes are indicated in hexagonal boxes.
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Conflict of interest
Author AFP has received research funding from Gnosis spa, and EUTox. DI holds a 3rd mission collaboration with Gnosis, spa through a contract stipulated with the Department of Precision Medicine, University “Luigi Vanvitelli”.
This article does not contain any studies with human participants or animals performed by any of the authors.
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