Resurgence of Serine: An Often Neglected but Indispensable Amino Acid

Abstract

Serine is generally classified as a nutritionally nonessential (dispensable) amino acid, but metabolically, serine is indispensible and plays an essential role in several cellular processes. Serine is the major source of one-carbon units for methylation reactions that occur via the generation of S-adenosylmethionine. The regulation of serine metabolism in mammalian tissues is thus of critical importance for the control of methyl group transfer. In addition to the well known role of D-serine in the brain, L-serine has recently been implicated in breast cancer and other tumors due in part to the genomic copy number gain for 3-phosphoglycerate dehydrogenase, the enzyme that controls the entry of glycolytic intermediates into the pathway of serine synthesis. Here, we review recent information regarding the synthesis of serine and the regulation of its metabolism and discuss the role played by phosphoenolpyruvate carboxykinase in this process.The regulation of methyl group transfer is critical in controlling cellular processes, ranging from the synthesis of key metabolic intermediates, such as creatine, phosphatidylcholine, and epinephrine, to the methylation of proteins, DNA, and RNA. Serine, a nutritionally nonessential amino acid, plays a key role in this process by providing one-carbon units to tetrahydrofolate (THF) 2 to form N 5 ,N 10 -methylene-THF and, subsequently, 5-methyl-THF, an intermediate in the methylation of homocysteine to methionine, via homocysteine methyltransferase (methionine synthase) (Fig. 1). This ensures sufficient methionine for optimal functioning of the methionine cycle and for synthesis of S-adenosylmethionine, the key methyl donor in all cells. The regulation of the cellular levels of S-adenosylmethionine in response to metabolic changes and the role of the enzyme glycine N-methyltransferase in this process have been discussed recently in a minireview by Luka et al. (1). This minireview was particularly timely because it details the pioneering work on methyl group transfer of Conrad Wagner and colleagues.Serine is also involved in the ultimate disposal of methionine carbon by condensing with homocysteine to form cystathionine, a reaction that is catalyzed by cystathionine ␤-synthase. Cystathionine is subsequently split into cysteine and ␣-ketobutyrate by cystathionine ␥-lyase. This cascade of cysteine synthesis has been termed the "transsulfuration pathway" (Fig. 1). Over the past decade, the importance of the two enzymes of this pathway in the generation of hydrogen sulfide has been recognized. In addition, the metabolism of serine has been linked to the growth of breast cancer cells (2). The scope of the metabolism of sulfur-containing compounds in the generation of hydrogen sulfide and the role of the latter in the control of blood pressure and the reduction of ischemia/reperfusion injury have been reviewed in detail elsewhere (3-6). Here, we focus on the key role of serine in methyl group transfer and the factors that regulate its metabolism. Metabolism of Serine in Vivo and Sour...

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