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, 287 (24), 19786-91

Resurgence of Serine: An Often Neglected but Indispensable Amino Acid


Resurgence of Serine: An Often Neglected but Indispensable Amino Acid

Satish C Kalhan et al. J Biol Chem.


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.


Pathways of serine metabolism in mammals. The pathways for the synthesis and metabolic fate of serine are shown. The intermediates in the pathways shown in blue are involved in the synthesis of serine, either from glucose via glycolysis or from the triose phosphate pool, where carbon is generated from citric acid cycle intermediates. The latter pathway involves PEPCK (step 1), which is a major cataplerotic enzyme in the synthesis of serine. The conversion of 3-phosphoglycerate to phosphohydroxypyruvate is catalyzed by the enzyme 3-phosphoglycerate dehydrogenase (step 2). The final steps in the synthesis of serine involve the transamination of phosphohydroxypyruvate to l-phosphoserine (step 3) and the conversion of l-phosphoserine into serine by phosphoserine phosphatase (step 4). The pathway involved in methyl group transfer is shown by the red arrows, and the transsulfuration pathway is shown in orange. OAA, oxalacetate; PEP, phosphoenolpyruvate; MS, methionine synthase; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; CβS, cystathionine β-synthase; CγL, cystathionine γ-lyase.
Quantitative estimates of serine flux in humans. The contribution of precursors to the synthesis of serine and the estimated contribution of serine to its degradation products in human subjects during fasting are presented. The units are μmol kg−1 h−1 (derived from the data in Refs. and 10). Please note that ∼72 μmol of serine disposal kg−1 h−1 are not accounted for in the figure. See the discussion in text.

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