Serine

Overview

L-serine is a nonessential amino acid in eukaryotic cells, used for protein synthesis and in producing phosphoglycerides, glycerides, sphingolipids, phosphatidylserine, and methylenetetrahydrofolate. Moreover, L-serine is the precursor of two relevant coagonists of NMDA receptors: glycine (through the enzyme serine hydroxymethyltransferase), which preferentially acts on extrasynaptic receptors and D-serine (through the enzyme serine racemase), dominant at synaptic receptors. (R1)

Serine is essential for cysteine and glutathione synthesis:

1. Homocysteine + Serine –> Cystathionine (which later becomes cysteine)
2. Serine –> Glycine + 1-carbon (glycine is used to form GSH)

Consequently, Serine is essential for heme synthesis also (R2).

Synthesis

Serine is synthesized from the glycolytic intermediate glycerate 3-P and the glutaminolytic intermediate glutamate thereby linking glycolysis and glutaminolysis.

Synthesis of Serine requires:

• Glutamate
• NAD+

Step 1. Phosphoglycerate Dehydrogenase (PHGDH)

NAD⁺ + 3-Phosphoglycerate (3-PG) –> 3-PHP + NADH + H⁺

Step 2. Phosphoserine aminotransferase (PSAT1)

Glutamate + 4-PHP –> 3-PS - aKG

Step 3. P-Serine Phosphatase (PSPH)

3-PS + H₂O –> L-Serine + Pi

Enzymes and genes

Serine as inhibitor

Serine inhibits Glutamine Synthetase (GS) - the enzyme that assimilates ammonia, producing glutamine from glutamate:

Serine and glycine inhibit glutamine synthetase. The rationale for such regulation probably involves purine synthesis. Purine synthesis requires serine, glycine, C1 units and glutamine. High serine and glycine may indicate purine sufficiency, and a diminished need for glutamine for purine synthesis. Almost half the glutamine synthesized is used for purine synthesis, if glutamine is not used for glutamate synthesis. (R3)

Serine inhibits Homoserine Dehydrogenase I and Threonine Deaminase

Serine also inhibits homoserine dehydrogenase I and threonine deaminase, which are required for isoleucine synthesis, and the third enzyme of methionine synthesis. (R3)

Serine inhibits 3-Phosphoglycerate Dehydrogenase (PHGDH)

Serine inhibits the activities of several enzymes, which suggests that the intracellular concentration of serine is tightly regulated.

Serine allosterically inhibits 3-phosphoglycerate dehydrogenase, the first enzyme of the major serine pathway. Serine, glycine, or the products of C1 metabolism do not affect the activity of any other enzyme of this pathway.

In contrast, the transcriptional regulation is complex and only partially understood. C1 sufficiency is sensed by a balance of homocysteine to S-adenosylmethionine.

These sensors control SHMT synthesis through MetR, an activator that binds homocysteine (a sensor of C1 deficiency), and MetJ, a repressor that binds S-adenosylmethionine (a sensor of C1 excess) and controls MetR synthesis. (R3)