Phosphoglycerate dehydrogenase

PHGDH
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2G76
Identifiers
Aliases	PHGDH, 3-PGDH, 3PGDH, HEL-S-113, NLS, PDG, PGAD, PGD, PGDH, PHGDHD, SERA, NLS1, Phosphoglycerate dehydrogenase
External IDs	OMIM: 606879 MGI: 1355330 HomoloGene: 39318 GeneCards: PHGDH
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1p12 Start 119,648,411 bp[1] End 119,744,218 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3|3 F2.2 Start 98,220,486 bp[2] End 98,247,306 bp[2]
RNA expression pattern Bgee Top expressed in pancreas salivary gland Right lobe of liver caudate nucleus amygdala nucleus accumbens putamen substantia nigra More reference expression data BioGPS More reference expression data
Gene ontology Molecular function oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor NAD binding phosphoglycerate dehydrogenase activity electron transfer activity oxidoreductase activity L-malate dehydrogenase activity Cellular component cytosol extracellular exosome Biological process L-serine biosynthetic process brain development metabolism cellular amino acid biosynthetic process electron transport chain cellular amino acid metabolic process glutamine metabolic process glycine metabolic process L-serine metabolic process threonine metabolic process gamma-aminobutyric acid metabolic process regulation of gene expression taurine metabolic process spinal cord development glial cell development neural tube development neurogenesis neuron projection development G1 to G0 transition Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	26227	236539
Ensembl	ENSG00000092621	ENSMUSG00000053398
UniProt	O43175	Q61753
RefSeq (mRNA)	NM_006623 NM_032692	NM_016966
RefSeq (protein)	NP_006614	NP_058662
Location (UCSC)	Chr 1: 119.65 – 119.74 Mb	Chr 3: 98.22 – 98.25 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Posphoglycerate dehydrogenase {PHGDH} is an enzyme that catalyzes the chemical reactions

3-phospho-D-glycerate + NAD⁺ ${\displaystyle \rightleftharpoons }$ 3-phosphonooxypyruvate + NADH + H⁺

2-hydroxyglutarate + NAD⁺ ${\displaystyle \rightleftharpoons }$ 2-oxoglutarate + NADH + H⁺

The two substrates of this enzyme are 3-phospho-D-glycerate and NAD⁺, whereas its 3 products are 3-phosphohydroxypyruvate, NADH, and H⁺

It is also possible that two substrates of this enzyme are 2-hydroxyglutarate and NAD⁺, whereas its 3 products are 2-oxoglutarate, NADH, and H⁺.

As of 2012, the most widely studied variants of PHGDH are from the E. coli and M. tuberculosis genomes.^[5] In humans, this enzyme is encoded by the PHGDH gene.^[6]

Function[]

3-Phosphoglycerate dehydrogenase catalyzes the transition of 3-phosphoglycerate into 3-phosphohydroxypyruvate, which is the committed step in the phosphorylated pathway of L-serine biosynthesis. It is also essential in cysteine and glycine synthesis, which lie further downstream.^[7] This pathway represents the only way to synthesize serine in most organisms except plants, which uniquely possess multiple synthetic pathways. Nonetheless, the phosphorylated pathway that PHGDH participates in is still suspected to have an essential role in serine synthesis used in the developmental signaling of plants.^[8][9]

Because of serine and glycine's role as neurotrophic factors in the developing brain, PHGDH has been shown to have high expression in glial and astrocyte cells during neural development.^[10]

Mechanism and regulation[]

3-phosphoglycerate dehydrogenase works via an induced fit mechanism to catalyze the transfer of a hydride from the substrate to NAD+, a required cofactor. In its active conformation, the enzyme's active site has multiple cationic residues that likely stabilize the transition state of the reaction between the negatively charged substrate and NAD⁺. The positioning is such that the substrate's alpha carbon and the C4 of the nicotinamide ring are brought into a proximity that facilitates the hydride transfer producing NADH and the oxidized substrate.^[5][11]

Active site of human PHGDH. Key residues (two Arg and one His) and substrates shown. The 4.2 Å distance is between the carbons undergoing hydride transfer. From 2G76 rendering of PHGDH crystallized with NAD⁺ and D-malate.

PHGDH is allosterically regulated by its downstream product, L-serine. This feedback inhibition is understandable considering that 3-phosphoglycerate is an intermediate in the glycolytic pathway. Given that PHGDH represents the committed step in the production of serine in the cell, flux through the pathway must be carefully controlled.

L-serine binding has been shown to exhibit cooperative behavior. Mutants that decreased this cooperativity also increased in sensitivity to serine's allosteric inhibition, suggesting a separation of the chemical mechanisms that result in allosteric binding cooperativity and active site inhibition.^[12] The mechanism of inhibition is Vmax type, indicating that serine affects the reaction rate rather than the binding affinity of the active site.^[11][13]

Although L-serine's allosteric effects are usually the focus of regulatory investigation, it has been noted that in some variants of the enzyme, 3-phosphoglycerate dehydrogenase is inhibited at separate positively charged allosteric site by high concentrations of its own substrate.^[5][14]

Structure[]

3-Phosphoglycerate dehydrogenase is a tetramer, composed of four identical, asymmetric subunits. At any time, only a maximum of two adjacent subunits present a catalytically active site; the other two are forced into an inactive conformation. This results in half-of-the-sites activity with regard to both active and allosteric sites, meaning that only the two sites of the active subunits must be bound for essentially maximal effect with regard to catalysis and inhibition respectively.^[15] There is some evidence that further inhibition occurs with the binding of the third and fourth serine molecules, but it is relatively minimal.^[13]

The subunits from the E. coli PHGDH have three distinct domains, whereas those from M. tuberculosis have four. It is noted that the human enzyme more closely resembles that of M. tuberculosis, including the site for allosteric substrate inhibition. Concretely, three general types of PHGDH have been proposed: Type I, II, and III. Type III has two distinct domains, lacks both allosteric sites, and is found in various unicellular organisms. Type II has serine binding sites and encompasses the well-studied E. coli PHGDH. Type I possesses both the serine and substrate allosteric binding sites and encompasses M. tuberculosis and mammalian PHGDHs.^[5]

The regulation of catalytic activity is thought to be a result of the movement of rigid domains about flexible “hinges.” When the substrate binds to the open active site, the hinge rotates and closes the cleft. Allosteric inhibition thus likely works by locking the hinge in a state that produces the open active site cleft.^[13][16]

Crystal structure of inhibited PHGDH from M. tuberculosis due to allosterically bound serine. From 3DC2 rendering.

The variant from M. tuberculosis also exhibits an uncommon dual pH optimum for catalytic activity.^[14]

Evolution[]

3-Phosphoglycerate dehydrogenase possesses less than 20% homology to other NAD-dependent oxidoreductases and exhibits significant variance between species. There does appear to be conservation in specific binding domain residues, but there is still some variation in the positively charged active site residues between variants. For example, Type III PHGDH enzymes can be broken down into two subclasses where the key histidine residue is replaced with a lysine residue.^[5][17]

Disease relevance[]

Homozygous or compound heterozygous mutations in 3-phosphoglycerate dehydrogenase cause Neu-Laxova syndrome^[18][19] and phosphoglycerate dehydrogenase deficiency.^[20] In addition significantly shortening lifespan, PHGDH deficiencies are known to cause congenital microcephaly, psychomotor retardation, and intractable seizures in both humans and rats, presumably due to the essential signaling within the nervous system that serine, glycine, and other downstream molecules are intimately involved with. Treatment typically involves oral supplementation of serine and glycine and has been shown most effective when started in utero via oral ingestion by the mother.^[21][22]

Mutations that result in increased PHGDH activity are also associated with increased risk of oncogenesis, including certain breast cancers.^[23] This finding suggests that pathways providing an outlet for diverting carbon out of glycolysis may be beneficial for rapid cell growth.^[24]

It has been reported that PHGDH can also catalyze the conversion of alpha-ketoglutarate to 2-Hydroxyglutaric acid in certain variants. Thus, a mutation in the enzyme is hypothesized to contribute to 2-Hydroxyglutaric aciduria in humans, although there is debate as to whether or not this catalysis is shared by human PHGDH.^[5][25]

References[]