Adenosine-the missing link to understanding homocysteine pathogenicity or more smoke on the horizon?

See article by Riksen et al. [8] (pages 271–276) in this reaction equilibrium will shift toward AdoHcy production issue. and simultaneously tend to lower the free Ado concenBased on epidemiological studies, homocysteine (Hcy) tration. Riksen and colleagues argue that because Ado has is regarded as an independent risk indicator for occlusive several well known, protective actions in the cardiovascuvascular diseases [1,2]. Under experimental conditions, lar system mediated by purine surface receptors [9,10], the increased Hcy concentrations have been found to result in increased removal of Ado, due to increased Hcy conendothelial dysfunction, leukocyte adhesion, and smooth centrations, would significantly lower the Ado concenmuscle and collagen proliferation [3–6]. However, the tration at these receptors and by diminishing the protective underlying molecular and metabolic links have not been actions potentially permit deleterious effects on the carconclusively elucidated [7]. Thus, it still remains to be diovascular system. determined whether Hcy indeed represents a risk factor or The hypothesis by Riksen et al. [8] is not the first rather a risk indicator. proposal that attempts to provide a rationale for underIn this issue of the Journal, Riksen et al. [8] present a standing the unfortunate effects that are often found to be new hypothesis on the relationship of Hcy and some of its associated with enhanced Hcy plasma levels. Previous presumed effects. This hypothesis is centered on the hypotheses that have been considered include (for a metabolism of Hcy with the purine adenosine (Ado) (Fig. metabolic scheme see Fig. 1): 1). Both metabolites originate in the cytosol from the reversible hydrolysis of S-adenosylhomocysteine 1. Hcy thiolactone, which is formed from Hcy by action of (AdoHcy) by the action of AdoHcy hydrolase: methionyl-tRNA synthetase, may lead to homocysteinylation of a variety of proteins, including AdoHcy1H O↔Hcy1Ado (1) 2 albumin, fibrinogen, or transferrin [11]. The reaction which takes place at lysine residues of proteins may Under normal physiological conditions, the net flux significantly decrease enzyme activities, as shown for through this pathway is toward Hcy and Ado production methionyl-tRNA synthetase, trypsin, and lysine oxidase because both compounds are rapidly metabolized, thus, [11]. Hcy thiolactone may be converted to Hcy by the their concentrations are kept low. In addition, AdoHcy is action of thiolactonase /paraoxonase, which is associcontinuously produced from S-adenosylmethionine ated with the high-density lipoprotein (HDL) fraction of (AdoMet) via the transmethylation pathway: serum lipoproteins. Recently, this enzyme activity was suggested to contribute to the protective role of the AdoMet1R→AdoHcy1R-CH (2) 3 HDL fraction against oxidative damage and Hcy toxicia reaction that is nonreversible under physiological conty [12]. ditions. However, the AdoHcy hydrolase-catalysed re2. Free Hcy has a thiol group that may interact with the action depends on the concentration of each of the thiol groups of proteins, forming disulfide bonds. Aside reactants AdoHcy, Hcy, and Ado (reaction (1)). Under from albumin, Hcy binding also has been shown with conditions when the Hcy concentration increases, the fibronectin where Hcy seems to bind mainly within or near the fibrin-binding domain, significantly reducing the fibrin binding capacity of the protein [13]. This *Tel.: 149-351-458-6030; fax: 149-351-458-6301. E-mail address: [email protected] (A. Deussen). suggests that Hcy may interfere with normal thrombosis