PHGDH

General Information

Full gene name:phosphoglycerate dehydrogenase
Entrez Gene ID:26227
Location:1p12
Synonyms:PGD, 3-PGDH, PGAD, PGDH, SERA, PDG, 3PGDH
Type:protein-coding

User SNPs

SNPs given by the user that are near or inside this gene:

SNP Distance (bp) Direction
rs10923931 231110 downstream

NCBI Summary

This gene encodes the enzyme which is involved in the early steps of L-serine synthesis in animal cells. L-serine is required for D-serine and other amino acid synthesis. The enzyme requires NAD/NADH as a cofactor and forms homotetramers for activity. Mutations in this gene have been found in a family with congenital microcephaly, psychomotor retardation and other symptoms. Multiple alternatively spliced transcript variants have been found, however the full-length nature of most are not known. [provided by RefSeq, Aug 2011]

OMIM

OMIM ID:`OMIM ID 606879 `_

Allelic Variants (Selected Examples)

.0001 PHOSPHOGLYCERATE DEHYDROGENASE DEFICIENCY

In 5 patients from 3 different families (2 Turkish and 1 European), Klomp et al. (2000) found that PHGDH deficiency (601815) was related to a homozygous 1468G-A transition predicted to cause a val490-to-met amino acid substitution in the protein.

.0002 PHOSPHOGLYCERATE DEHYDROGENASE DEFICIENCY

In a girl whose parents were a consanguineous Moroccan couple, reported by Pineda et al. (2000) as phosphoglycerate dehydrogenase deficiency (601815) in a case of West syndrome, Klomp et al. (2000) found a homozygous mutation, 1273G-A (val425 to met), in the PHGDH gene.

.0003 PHOSPHOGLYCERATE DEHYDROGENASE DEFICIENCY

In a Dutch boy with phosphoglycerate dehydrogenase deficiency (601815), Tabatabaie et al. (2009) identified compound heterozygosity for a 1-bp deletion (712delG) in exon 7 and a 403C-T transition in exon 4 of the PHGDH gene, the former causing a frameshift and premature termination codon and the latter resulting in an arg135-to-trp (R135W; 606879.0004) substitution. Analysis of enzyme kinetics in patient-derived fibroblasts showed a markedly decreased V(max). Transfection studies in HEK293 cells with the deletion mutant resulted in undetectable expression of 3-PGDH protein, whereas overexpression of the R135W mutant resulted in a moderate decrease of V(max) without affecting K(m). Molecular modeling of the R135W mutation onto the partial crystal structure of 3-PGDH predicted that the mutation would affect substrate and cofactor binding.

.0004 PHOSPHOGLYCERATE DEHYDROGENASE DEFICIENCY

See 606879.0003 and Tabatabaie et al. (2009).

.0005 PHOSPHOGLYCERATE DEHYDROGENASE DEFICIENCY

In a Dutch brother and sister with phosphoglycerate dehydrogenase deficiency (601815), born of consanguineous parents, Tabatabaie et al. (2009) identified homozygosity for a 1129G-A transition in exon 10 of the PHGDH gene, resulting in a gly377-to-ser (G377S) substitution. Analysis of enzyme kinetics in patient-derived fibroblasts showed a markedly decreased V(max); transfection studies in HEK293 cells with overexpression of the G377S mutant resulted in a moderate decrease of V(max) without affecting K(m).

.0006 PHOSPHOGLYCERATE DEHYDROGENASE DEFICIENCY

In a Turkish boy with phosphoglycerate dehydrogenase deficiency (601815), Tabatabaie et al. (2009) identified homozygosity for a 781G-A transition in exon 7 of the PHGDH gene, resulting in a val261-to-met (V261M) substitution. Analysis of enzyme kinetics in patient-derived fibroblasts showed a significant but incomplete reduction in V(max), whereas transfection studies in HEK293 cells with overexpression of the V261M mutant displayed a 4-fold increase in K(m). Molecular modeling of the V261M mutation onto the partial crystal structure of 3-PGDH predicted that the mutation would affect substrate and cofactor binding.

NCBI Phenotypes

  • Gene Reviews
  • Phosphoglycerate dehydrogenase deficiency
  • GTR
  • OMIM
  • Human metabolic individuality in biomedical and pharmaceutical research.
  • NHGRI GWA Catalog

Gene Ontology

  • cell cycle process
  • NAD binding
  • neuron projection development
  • cytosol
  • cellular amino acid biosynthetic process
  • regulation of gene expression
  • brain development
  • neural tube development
  • threonine metabolic process
  • glycine metabolic process
  • glutamine metabolic process
  • cellular nitrogen compound metabolic process
  • glial cell development
  • small molecule metabolic process
  • electron carrier activity
  • spinal cord development
  • L-serine biosynthetic process
  • taurine metabolic process
  • gamma-aminobutyric acid metabolic process
  • phosphoglycerate dehydrogenase activity

GeneRIFs

  • The potential mechanisms by which PHGDH promotes cancer are discussed. [PMID 21981974]
  • results reveal that certain breast cancers are dependent upon increased serine pathway flux caused by PHGDH overexpression and demonstrate the utility of in vivo negative-selection RNAi screens for finding potential anticancer targets [PMID 21760589]
  • These data suggest that missense mutations associated with 3-PGDH deficiency either primarily affect substrate binding or result in very low residual enzymatic activity. [PMID 19235232]
  • Affinity Capture-MS [PMID 21081666]
  • Affinity Capture-MS [PMID 17643375]
  • Two-hybrid [PMID 21900206]
  • we conclude that this mutation impairs the folding and/or assembly of PHGDH but has minimal effects on the activity or stability of that portion of the V490M mutant that reaches a mature conformation [PMID 11751922]
  • Affinity Capture-MS [PMID 19596686]
  • in some cancer cells a relatively large amount of glycolytic carbon is diverted into serine and glycine metabolism through phosphoglycerate dehydrogenase. [PMID 21804546]
  • A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. [PMID 22360420]
  • Studies in bacteria showed that addition of substrate at the active site is ordered, with HPAP binding before NADH. Also, NADH can compete with the substrate for binding to the allosteric site and thereby eliminate the substrate inhibition. [PMID 19388702]
  • Affinity Capture-MS; Co-purification [PMID 21987572]
  • Affinity Capture-MS [PMID 20360068]
  • Affinity Capture-MS [PMID 20360068]
  • Affinity Capture-MS [PMID 20360068]
  • Affinity Capture-MS [PMID 20360068]
  • Affinity Capture-MS [PMID 16236267]
  • PHGDH is expressed in cytoplasm of stromal and glandular cells in endometrium; expression is relatively high in proliferative phase and lower in secretory phase. Data suggest expression of PHGDH in endometrium is regulated by HOXA10. [PMID 19778996]
  • The frequency of antibodies to Phgdh is much higher in patients with autoimmune hepatitis than in patients with other types of hepatitis or normal controls. [PMID 19497206]
  • The crystal structure of Mycobacterium tuberculosis D-3-phosphoglycerate dehydrogenase has been solved with bound effector, 1-serine, and substrate, hydroxypyruvic acid phosphate. The human enzyme was also examined. [PMID 18627175]
  • a coding PHGDH SNP (rs543703) was weakly associated with the development of schizophrenia in Korean population [PMID 19404161]
  • Observational study of gene-disease association. (HuGE Navigator) [PMID 19223009]
  • Affinity Capture-MS [PMID 19135240]

PubMed Articles

Recent articles:

  • Martins-de-Souza D et al. “Proteomic analysis identifies dysfunction in cellular transport, energy, and protein metabolism in different brain regions of atypical frontotemporal lobar degeneration.” J Proteome Res. 2012 Apr 6;11(4):2533-43. PMID 22360420
  • Lee KA et al. “Ubiquitin ligase substrate identification through quantitative proteomics at both the protein and peptide levels.” J Biol Chem. 2011 Dec 2;286(48):41530-8. PMID 21987572
  • Mullarky E et al. “PHGDH amplification and altered glucose metabolism in human melanoma.” Pigment Cell Melanoma Res. 2011 Dec;24(6):1112-5. PMID 21981974
  • Kim W et al. “Systematic and quantitative assessment of the ubiquitin-modified proteome.” Mol Cell. 2011 Oct 21;44(2):325-40. PMID 21906983
  • Emanuele MJ et al. “Global identification of modular cullin-RING ligase substrates.” Cell. 2011 Oct 14;147(2):459-74. PMID 21963094
  • Wagner SA et al. “A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.” Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. PMID 21890473
  • Vinayagam A et al. “A directed protein interaction network for investigating intracellular signal transduction.” Sci Signal. 2011 Sep 6;4(189):rs8. PMID 21900206
  • Suhre K et al. “Human metabolic individuality in biomedical and pharmaceutical research.” Nature. 2011 Aug 31;477(7362):54-60. PMID 21886157
  • Possemato R et al. “Functional genomics reveal that the serine synthesis pathway is essential in breast cancer.” Nature. 2011 Aug 18;476(7360):346-50. PMID 21760589
  • Locasale JW et al. “Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis.” Nat Genet. 2011 Jul 31;43(9):869-74. PMID 21804546

Top Pubmed articles linked to gene PHGDH matching any search term:

  • Nilsson LM et al. “Mouse genetics suggests cell-context dependency for Myc-regulated metabolic enzymes during tumorigenesis.” PLoS Genet. 2012 Mar;8(3):e1002573. PMID 22438825
  • Mullarky E et al. “PHGDH amplification and altered glucose metabolism in human melanoma.” Pigment Cell Melanoma Res. 2011 Dec;24(6):1112-5. PMID 21981974
  • Suhre K et al. “Human metabolic individuality in biomedical and pharmaceutical research.” Nature. 2011 Aug 31;477(7362):54-60. PMID 21886157
  • Locasale JW et al. “Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis.” Nat Genet. 2011 Jul 31;43(9):869-74. PMID 21804546
  • Bollig-Fischer A et al. “Oncogene activation induces metabolic transformation resulting in insulin-independence in human breast cancer cells.” PLoS One. 2011 Mar 17;6(3):e17959. PMID 21437235
  • Sumara G et al. “Regulation of PKD by the MAPK p38delta in insulin secretion and glucose homeostasis.” Cell. 2009 Jan 23;136(2):235-48. PMID 19135240
  • Guo D et al. “Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress.” Biochem Biophys Res Commun. 2005 Dec 2;337(4):1308-18. PMID 16236267

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