Regulation of Methionine Biosynthesis

Methionine is a sulfur-containing essential amino acid, a building block of proteins that also plays a fundamental role in many cellular processes. Through its immediate catabolic product S-adenosyl methionine (SAM), methionine is a precursor for the plant hormones ethylene and polyamines as well as for many important secondary metabolites and vitamin B1. SAM is also a donor of a methyl group to a number of cellular reactions, such as DNA methylation (Amir et al., 2002 and references therein). In plants, methionine can be converted into S-methylmethionine (SMM), a metabolite that is believed to participate in sulfur transport between sink and source tissues (Bourgis et al., 1999), and also to control the intracellular levels of SAM (Kocsis et al., 2003; Ranocha et al., 2001). Due to its vital cellular importance, the methionine level is tightly regulated both by its synthesis and catabolism. Methionine is an unstable amino acid with a very fast half-life (Giovanelli et al., 1985; Miyazaki and Yang, 1987).

Methionine receives its carbon and amino groups from O-phosphohomoserine, an intermediate metabolite in the aspartate family pathway, and its sulfur atom from cysteine (Fig. 3.2). These two skeleta are first combined by the enzyme cystathionine γ-synthase (CGS) to form cystathionine. This is then converted by cystathionine β-lyase into homocysteine, and converted by methionine synthase into methionine, incorporating a methyl group from N-methyltetrahydrofolate (Fig. 3.2). Hence, the complex biosynthesis nature of methionine depends on many regulatory metabolic steps, including the aspartate family pathway, cysteine biosynthesis, and N-methyltetrahydrofolate metabolism. Nevertheless, molecular genetic and biochemical studies suggest that methionine biosynthesis is regulated primarily by CGS as well as by a compound metabolic interaction with threonine synthesis through a competition between CGS and threonine synthase (TS) on their common substrate O-phosphohomoserine (Fig. 3.2).

FIGURE 3.2 Schematic diagram of the metabolic network containing the aspartate family pathway, methionine metabolism, and last two steps in the cysteine biosynthesis. Only some of the enzymes and metabolites are specified. Abbreviations: AK, aspartate kinase; DHPS, dihydrodipicolinate synthase; HSD, homoserine dehydrogenase; HK, homoserine kinase; TS, threonine synthase; TDH, threonine dehydratase; SAT, serine acetyl transferase; OAS (thio) lyase; O-acetyl serine (thio) lyase; CGS, cystathionine γ-synthase; CBL, cystathionine β-lyase; MS, methionine synthase, SAM, S-adenosyl methionine; SAMS, S-adenosyl methionine synthase; AdoHcys, adenosylhomocysteine; SMM, S-methyl methionine; MTHF, methyltetrahydrofolate. Dashed arrows with a ‘‘minus’’ sign represent feedback inhibition loops of key enzymes in the network. The dashed and dotted arrow with the ‘‘plus’’ sign represents the stimulation of TS activity by SAM.