Homocysteine-a retrospective and prospective appraisal

Abstract

The biologically important amino acid homocysteine links sulfur, methionine, and one-carbon metabolism. This review describes its initial discovery, the identification of the clinical condition of "homocystinuria" and the recognition of its close relationship to folate and vitamin B12 metabolism. It discusses the history behind its current association with diverse diseases including neural tube defects, cardio- and cerebrovascular disease and, more recently, dementia and Alzheimer's Disease. It also explores current controversies and considers potential future research directions. It is intended to give a general overview of homocysteine in relation to health and disease.

Keywords: Alzheimer’s disease; dementia; folate; homocysteine; inborn errors of metabolism; neural tube defects; vascular disease; vitamin B12.

Figure 1

Homocysteine and related sulfur amino acids. Homocysteine, cysteine, and methionine are related amino acids that all contain a sulfur atom in their sidechains. Dietary methionine is converted to homocysteine and to cysteine via the transsulfuration pathway (see Figure 2). In the blood, homocysteine exists in several forms, including the free reduced form (no disulfide bond), homocystine (disulfide bond between two homocysteine molecules), mixed-disulfide (disulfide bond between homocysteine and cysteine), and protein-bound (disulfide bond between homocysteine and a cysteine within a protein such as albumin). Hcy, homocysteine; Cys, cysteine.

Figure 2

Homocysteine metabolism: interrelationships among the methylation cycle, the transsulfuration pathway, and the folate cycle. Homocysteine is a product of the methylation cycle in which dietary methionine is activated by the addition of an adenosyl group from ATP to form S-adenosylmethionine (SAM). SAM then donates a methyl group to one of a variety of methyl acceptors, such as DNA, RNA, histones, proteins, membrane phospholipids, neurotransmitters, and guanidinoacetate. S-adenosylhomocysteine is produced as a product, which then loses its adenosine group to form homocysteine. Homocysteine can then be converted back to methionine by methionine synthase (1) with methyltetrahydrofolate (MethylTHF) serving as the methyl donor and vitamin B12 serving as a cofactor (occurring in all tissues), or by betaine-homocysteine methyltransferase (2) with betaine (a product of choline metabolism) serving as the methyl donor (occurring only in the liver and kidneys). MethylTHF is produced in the folate cycle by the reduction of methylenetetrahydrofolate (methyleneTHF) catalyzed by the enzyme methylenetetrahydrofolate reductase or MTHFR (4), a FAD (riboflavin)-dependent enzyme. Alternatively, homocysteine can be catabolized through the transsulfuration pathway to cystathionine by the enzyme cystathionine β-synthase (3) and then cysteine by the enzyme cystathionine γ-lyase (5), two vitamin B6 or pyridoxal-5′-phosphate (PLP)-dependent reactions. Further metabolism of cysteine produces the antioxidant glutathione among other products. Whether homocysteine is remethylated back to methionine or catabolized via transulfuration is in part regulated by SAM through allosteric activation of cystathionine β-synthase (3) and allosteric inhibition of MTHFR (4). Modified from Miller (1).

Figure 3

Intracellular vitamin B12 metabolism. Vitamin B12 is taken up by cells bound to transcobalamin (TC) via the transcobalamin receptor (also known as CD320). The TC and B12 are disassociated in the lysosome, and then B12 is transported into the cytoplasm where it is metabolized to form methylcobalamin (Methyl-B12) or into the mitochondria where it is metabolized to form 5-deoxyadenosylcobalamin (Adenosyl-B12). The transport and metabolism of B12 is carried by a variety of proteins that are designated as cblA—cblG, cblJ, and mut (not pictured are two additional proteins, cblK and cblX, which act in the nucleus). Genetic defects in several of these proteins inhibit B12 processing and can lead to homocystinuria. Modified from Rosenblatt (39).