RBCC Red Blood Cell Collection

PHGDH (PGDH3) [Confidence: low (only semi-automatic identification from reviews)]
D-3-phosphoglycerate dehydrogenase; 3-PGDH; 1.1.1.95
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt O43175
ID SERA_HUMAN Reviewed; 533 AA.
AC O43175; B2RD08; Q5SZU3; Q9BQ01;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 4.
DT 22-JAN-2014, entry version 143.
DE RecName: Full=D-3-phosphoglycerate dehydrogenase;
DE Short=3-PGDH;
DE EC=1.1.1.95;
GN Name=PHGDH; Synonyms=PGDH3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=10713460; DOI=10.1016/S0378-1119(00)00009-3;
RA Cho H.M., Jun D.Y., Bae M.A., Ahn J.D., Kim Y.H.;
RT "Nucleotide sequence and differential expression of the human 3-
RT phosphoglycerate dehydrogenase gene.";
RL Gene 245:193-201(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS PHGDH DEFICIENCY MET-425 AND
RP MET-490.
RX PubMed=11055895; DOI=10.1086/316886;
RA Klomp L.W.J., de Koning T.J., Malingre H.E.M., van Beurden E.A.C.M.,
RA Brink M., Opdam F.L., Duran M., Jaeken J., Pineda M.,
RA van Maldergem L., Poll-The B.T., van den Berg I.E.T., Berger R.;
RT "Molecular characterization of 3-phosphoglycerate dehydrogenase
RT deficiency -- a neurometabolic disorder associated with reduced L-
RT serine biosynthesis.";
RL Am. J. Hum. Genet. 67:1389-1399(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, Lung, and Muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP PROTEIN SEQUENCE OF 2-54; 59-69; 76-119; 138-155; 237-289; 295-308;
RP 352-380; 385-394; 462-491 AND 523-533, CLEAVAGE OF INITIATOR
RP METHIONINE, ACETYLATION AT ALA-2, AND MASS SPECTROMETRY.
RC TISSUE=B-cell lymphoma, and Ovarian carcinoma;
RA Bienvenut W.V.;
RL Submitted (JAN-2010) to UniProtKB.
RN [9]
RP PROTEIN SEQUENCE OF 9-20; 22-33; 76-90; 248-268 AND 271-289.
RC TISSUE=Fetal brain cortex;
RA Lubec G., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [10]
RP CATALYTIC ACTIVITY, AND VARIANT MET-490.
RX PubMed=11751922; DOI=10.1074/jbc.M111419200;
RA Pind S., Slominski E., Mauthe J., Pearlman K., Swoboda K.J.,
RA Wilkins J.A., Sauder P., Natowicz M.R.;
RT "V490M, a common mutation in 3-phosphoglycerate dehydrogenase
RT deficiency, causes enzyme deficiency by decreasing the yield of mature
RT enzyme.";
RL J. Biol. Chem. 277:7136-7143(2002).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY, AND INDUCTION BY
RP 17-BETA-ESTRADIOL AND 4-HYDROXYTAMOXIFEN.
RX PubMed=16949628; DOI=10.1016/j.steroids.2006.07.006;
RA Al-Dhaheri M.H., Shah Y.M., Basrur V., Pind S., Rowan B.G.;
RT "Identification of novel proteins induced by estradiol, 4-
RT hydroxytamoxifen and acolbifene in T47D breast cancer cells.";
RL Steroids 71:966-978(2006).
RN [12]
RP INDUCTION BY SP1 AND NF-Y.
RX PubMed=18378410; DOI=10.1016/j.gene.2008.02.018;
RA Jun D.Y., Park H.S., Lee J.Y., Baek J.Y., Park H.-K., Fukui K.,
RA Kim Y.H.;
RT "Positive regulation of promoter activity of human 3-phosphoglycerate
RT dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1
RT and NF-Y.";
RL Gene 414:106-114(2008).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 4-314 IN COMPLEX WITH NAD AND
RP SUBSTRATE.
RG Structural genomics consortium (SGC);
RT "Crystal structure of human 3-phosphoglycerate dehydrogenase.";
RL Submitted (FEB-2009) to the PDB data bank.
RN [16]
RP VARIANTS PHGDH DEFICIENCY TRP-135; MET-261; THR-373 AND SER-377,
RP CHARACTERIZATION OF VARIANTS PHGDH DEFICIENCY TRP-135; MET-261;
RP THR-373; SER-377; MET-425 AND MET-490, AND BIOPHYSICOCHEMICAL
RP PROPERTIES.
RX PubMed=19235232; DOI=10.1002/humu.20934;
RA Tabatabaie L., de Koning T.J., Geboers A.J.J.M., van den Berg I.E.T.,
RA Berger R., Klomp L.W.J.;
RT "Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are
RT distributed throughout the protein and result in altered enzyme
RT kinetics.";
RL Hum. Mutat. 30:749-756(2009).
CC -!- CATALYTIC ACTIVITY: 3-phospho-D-glycerate + NAD(+) = 3-
CC phosphonooxypyruvate + NADH.
CC -!- CATALYTIC ACTIVITY: 2-hydroxyglutarate + NAD(+) = 2-oxoglutarate +
CC NADH.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=21.6 uM for 3-phosphohydroxypyruvate;
CC Vmax=35 nmol/min/mg enzyme with 3-phosphohydroxypyruvate as
CC substrate (in patient-derived fibroblasts);
CC Vmax=168 nmol/min/mg enzyme with 3-phosphohydroxypyruvate as
CC substrate (in 3-PGDH overexpressed cells);
CC -!- PATHWAY: Amino-acid biosynthesis; L-serine biosynthesis; L-serine
CC from 3-phospho-D-glycerate: step 1/3.
CC -!- SUBUNIT: Homotetramer (By similarity).
CC -!- INDUCTION: Induced by 17-beta-estradiol (estrogenic ligand) and 4-
CC hydroxytamoxifen (agonist/antagonist ligand). Positively regulated
CC by the transcription factors SP1 and NF-Y.
CC -!- DISEASE: Phosphoglycerate dehydrogenase deficiency (PHGDH
CC deficiency) [MIM:601815]: Characterized by congenital
CC microcephaly, psychomotor retardation, and seizures. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the D-isomer specific 2-hydroxyacid
CC dehydrogenase family.
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DR EMBL; AF006043; AAB88664.1; -; mRNA.
DR EMBL; AF171237; AAD51415.1; -; mRNA.
DR EMBL; CR456795; CAG33076.1; -; mRNA.
DR EMBL; AK315360; BAG37755.1; -; mRNA.
DR EMBL; AL589734; CAI22407.1; -; Genomic_DNA.
DR EMBL; AL139251; CAI22407.1; JOINED; Genomic_DNA.
DR EMBL; AL139251; CAI22212.1; -; Genomic_DNA.
DR EMBL; AL589734; CAI22212.1; JOINED; Genomic_DNA.
DR EMBL; CH471122; EAW56708.1; -; Genomic_DNA.
DR EMBL; BC000303; AAH00303.1; -; mRNA.
DR EMBL; BC001349; AAH01349.1; -; mRNA.
DR EMBL; BC011262; AAH11262.1; -; mRNA.
DR RefSeq; NP_006614.2; NM_006623.3.
DR UniGene; Hs.487296; -.
DR PDB; 2G76; X-ray; 1.70 A; A/B=4-314.
DR PDBsum; 2G76; -.
DR ProteinModelPortal; O43175; -.
DR SMR; O43175; 6-307.
DR IntAct; O43175; 21.
DR MINT; MINT-4999739; -.
DR STRING; 9606.ENSP00000358417; -.
DR ChEMBL; CHEMBL2311243; -.
DR DrugBank; DB00157; NADH.
DR PhosphoSite; O43175; -.
DR PaxDb; O43175; -.
DR PeptideAtlas; O43175; -.
DR PRIDE; O43175; -.
DR DNASU; 26227; -.
DR Ensembl; ENST00000369409; ENSP00000358417; ENSG00000092621.
DR GeneID; 26227; -.
DR KEGG; hsa:26227; -.
DR UCSC; uc001ehz.3; human.
DR CTD; 26227; -.
DR GeneCards; GC01P120202; -.
DR HGNC; HGNC:8923; PHGDH.
DR HPA; CAB003681; -.
DR HPA; HPA021241; -.
DR HPA; HPA024031; -.
DR MIM; 601815; phenotype.
DR MIM; 606879; gene.
DR neXtProt; NX_O43175; -.
DR Orphanet; 79351; 3-phosphoglycerate dehydrogenase deficiency.
DR PharmGKB; PA33264; -.
DR eggNOG; COG0111; -.
DR HOGENOM; HOG000136693; -.
DR HOVERGEN; HBG054241; -.
DR InParanoid; O43175; -.
DR KO; K00058; -.
DR OMA; NDNTFAQ; -.
DR OrthoDB; EOG7JT6WT; -.
DR PhylomeDB; O43175; -.
DR BioCyc; MetaCyc:HS01776-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00135; UER00196.
DR ChiTaRS; PHGDH; human.
DR EvolutionaryTrace; O43175; -.
DR GeneWiki; Phosphoglycerate_dehydrogenase; -.
DR GenomeRNAi; 26227; -.
DR NextBio; 48383; -.
DR PRO; PR:O43175; -.
DR ArrayExpress; O43175; -.
DR Bgee; O43175; -.
DR CleanEx; HS_PHGDH; -.
DR Genevestigator; O43175; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0009055; F:electron carrier activity; TAS:UniProtKB.
DR GO; GO:0051287; F:NAD binding; IEA:InterPro.
DR GO; GO:0004617; F:phosphoglycerate dehydrogenase activity; TAS:Reactome.
DR GO; GO:0007420; P:brain development; TAS:ProtInc.
DR GO; GO:0022402; P:cell cycle process; IEA:Ensembl.
DR GO; GO:0034641; P:cellular nitrogen compound metabolic process; TAS:Reactome.
DR GO; GO:0009448; P:gamma-aminobutyric acid metabolic process; IEA:Ensembl.
DR GO; GO:0021782; P:glial cell development; IEA:Ensembl.
DR GO; GO:0006541; P:glutamine metabolic process; IEA:Ensembl.
DR GO; GO:0006544; P:glycine metabolic process; IEA:Ensembl.
DR GO; GO:0006564; P:L-serine biosynthetic process; TAS:Reactome.
DR GO; GO:0021915; P:neural tube development; IEA:Ensembl.
DR GO; GO:0031175; P:neuron projection development; IEA:Ensembl.
DR GO; GO:0010468; P:regulation of gene expression; IEA:Ensembl.
DR GO; GO:0021510; P:spinal cord development; IEA:Ensembl.
DR GO; GO:0019530; P:taurine metabolic process; IEA:Ensembl.
DR GO; GO:0006566; P:threonine metabolic process; IEA:Ensembl.
DR Gene3D; 3.40.50.720; -; 2.
DR InterPro; IPR006236; D-3-Phosphoglycerate_DH.
DR InterPro; IPR006139; D-isomer_2_OHA_DH_cat_dom.
DR InterPro; IPR006140; D-isomer_2_OHA_DH_NAD-bd.
DR InterPro; IPR016040; NAD(P)-bd_dom.
DR PANTHER; PTHR10996:SF20; PTHR10996:SF20; 1.
DR Pfam; PF00389; 2-Hacid_dh; 1.
DR Pfam; PF02826; 2-Hacid_dh_C; 1.
DR TIGRFAMs; TIGR01327; PGDH; 1.
DR PROSITE; PS00065; D_2_HYDROXYACID_DH_1; 1.
DR PROSITE; PS00670; D_2_HYDROXYACID_DH_2; 1.
DR PROSITE; PS00671; D_2_HYDROXYACID_DH_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Amino-acid biosynthesis; Complete proteome;
KW Direct protein sequencing; Disease mutation; NAD; Oxidoreductase;
KW Reference proteome; Serine biosynthesis.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 533 D-3-phosphoglycerate dehydrogenase.
FT /FTId=PRO_0000076012.
FT NP_BIND 155 156 NAD.
FT NP_BIND 234 236 NAD.
FT NP_BIND 283 286 NAD.
FT ACT_SITE 236 236
FT ACT_SITE 265 265 By similarity.
FT ACT_SITE 283 283 Proton donor.
FT BINDING 78 78 NAD.
FT BINDING 175 175 NAD.
FT BINDING 207 207 NAD; via carbonyl oxygen.
FT BINDING 260 260 NAD.
FT MOD_RES 2 2 N-acetylalanine.
FT VARIANT 135 135 R -> W (in PHGDH deficiency; results in a
FT 2-fold decrease in enzyme activity with
FT 3-phosphohydroxypyruvate, but no change
FT in substrate affinity).
FT /FTId=VAR_059026.
FT VARIANT 261 261 V -> M (in PHGDH deficiency; results in a
FT four-fold decrease in substrate affinity
FT and a slight increase in maximal enzyme
FT activity with 3-phosphohydroxypyruvate).
FT /FTId=VAR_059027.
FT VARIANT 373 373 A -> T (in PHGDH deficiency; results in
FT almost undetectable enzyme activity with
FT 3-phosphohydroxypyruvate).
FT /FTId=VAR_059028.
FT VARIANT 377 377 G -> S (in PHGDH deficiency; results in a
FT 2-fold decrease in enzyme activity with
FT 3-phosphohydroxypyruvate, but no change
FT in substrate affinity).
FT /FTId=VAR_059029.
FT VARIANT 425 425 V -> M (in PHGDH deficiency; results in
FT almost undetectable enzyme activity with
FT 3-phosphohydroxypyruvate).
FT /FTId=VAR_013461.
FT VARIANT 490 490 V -> M (in PHGDH deficiency; results in
FT almost undetectable enzyme activity with
FT 3-phosphohydroxypyruvate;
FT dbSNP:rs121907987).
FT /FTId=VAR_059030.
FT CONFLICT 25 25 D -> E (in Ref. 1; AAB88664/AAD51415).
FT STRAND 8 11
FT HELIX 18 26
FT STRAND 29 32
FT HELIX 38 44
FT HELIX 45 47
FT STRAND 49 53
FT STRAND 55 57
FT HELIX 61 66
FT STRAND 72 79
FT HELIX 85 91
FT STRAND 94 96
FT HELIX 103 119
FT HELIX 121 129
FT HELIX 136 138
FT STRAND 147 151
FT HELIX 155 165
FT TURN 166 168
FT STRAND 170 174
FT STRAND 176 178
FT HELIX 180 185
FT HELIX 193 196
FT HELIX 197 199
FT STRAND 201 205
FT TURN 211 215
FT HELIX 219 222
FT STRAND 229 233
FT HELIX 242 251
FT STRAND 252 260
FT STRAND 263 266
FT HELIX 271 274
FT STRAND 278 280
FT HELIX 289 306
SQ SEQUENCE 533 AA; 56651 MW; C58EB72275C45B35 CRC64;
MAFANLRKVL ISDSLDPCCR KILQDGGLQV VEKQNLSKEE LIAELQDCEG LIVRSATKVT
ADVINAAEKL QVVGRAGTGV DNVDLEAATR KGILVMNTPN GNSLSAAELT CGMIMCLARQ
IPQATASMKD GKWERKKFMG TELNGKTLGI LGLGRIGREV ATRMQSFGMK TIGYDPIISP
EVSASFGVQQ LPLEEIWPLC DFITVHTPLL PSTTGLLNDN TFAQCKKGVR VVNCARGGIV
DEGALLRALQ SGQCAGAALD VFTEEPPRDR ALVDHENVIS CPHLGASTKE AQSRCGEEIA
VQFVDMVKGK SLTGVVNAQA LTSAFSPHTK PWIGLAEALG TLMRAWAGSP KGTIQVITQG
TSLKNAGNCL SPAVIVGLLK EASKQADVNL VNAKLLVKEA GLNVTTSHSP AAPGEQGFGE
CLLAVALAGA PYQAVGLVQG TTPVLQGLNG AVFRPEVPLR RDLPLLLFRT QTSDPAMLPT
MIGLLAEAGV RLLSYQTSLV SDGETWHVMG ISSLLPSLEA WKQHVTEAFQ FHF
//

MIM 601815
*RECORD*
*FIELD* NO
601815
*FIELD* TI
#601815 PHOSPHOGLYCERATE DEHYDROGENASE DEFICIENCY
;;PHGDH DEFICIENCY
*FIELD* TX
A number sign (#) is used with the entry because the disorder is caused
read moreby homozygous or compound heterozygous or homozygous mutation in the
gene encoding phosphoglycerate dehydrogenase (PHGDH; 606879) on
chromosome 1p12.

DESCRIPTION

PHGDH deficiency is a disorder of L-serine biosynthesis that is
characterized by congenital microcephaly, psychomotor retardation, and
seizures.

CLINICAL FEATURES

Jaeken et al. (1996) described the clinical and biochemical features of
2 Turkish brothers who had a defect in the first enzyme of serine
biosynthesis (phosphoglycerate dehydrogenase). The sibs were born from a
first-cousin union. The authors noted that serine cerebrospinal fluid
concentrations were markedly decreased, as were, to a lesser extent,
glycine levels. Both sibs exhibited postnatal growth retardation,
congenital microcephaly, hypogonadism, and hypertonia, and later showed
profound psychomotor retardation and epilepsy. Magnetic resonance
imaging of the brain showed evidence of 'dysmyelination.' Symmetric
growth retardation at birth and bilateral congenital cataracts were
present in 1 brother. Notably, plasma serine and glycine values were
occasionally in the normal value range, as were urine organic acids and
amino acids. Ophthalmologic examination of the second brother was
normal. Decreased activity of phosphoglycerate dehydrogenase in
fibroblasts was noted in both sibs (22% and 13% when compared to
controls). Neither the parents nor the normal sibs were tested. Jaeken
et al. (1996) noted that although serine is a nonessential amino acid,
as it can be synthesized de novo from phosphoglycerate as well as
glycine, it appears essential for normal brain function as it plays a
role in the biosynthetic reactions of brain constituents such as
protein, glycine, cysteine, serine phospholipids, sphingomyelins, and
cerebrosides. The authors compared this enzyme deficiency to other
'anabolic' aminoacidopathies such as arginase deficiency (207800) in the
urea cycle, homocysteinemia, and phenylketonuria (261600) and contrasted
it with the more common 'catabolic' defects of amino acid metabolism.

CLINICAL MANAGEMENT

Jaeken et al. (1996) found that treatment with oral serine significantly
increased cerebrospinal fluid serine concentrations in a dose-dependent
manner and was coincident with the cessation of seizures (at a dose of
200 mg/kg/day divided into 3 doses) in 1 affected sib.

De Koning et al. (2002) reported the follow-up data of amino acid
therapy in 5 patients with 3-phosphoglycerate dehydrogenase (3-PGDH)
deficiency followed for 3 to 7.5 years. Different treatment regimes were
used, but a favorable response to amino acids was observed in all
patients. A major reduction in seizure frequency occurred in all
patients; 2 patients became seizure free. Amino acids were well
tolerated, with no adverse effects documented. The progress of
psychomotor development was only observed in 1 patient, diagnosed early,
and treated with a high dose of L-serine.

De Koning et al. (2004) reported the prenatal diagnosis of an affected
fetus with the V90M mutation (606879.0001) in the PHGDH gene. Ultrasound
assessment showed a reduction of fetal head circumference in the 75th
percentile at 20 weeks' gestation to the 29th percentile at 26 weeks'
gestation. L-serine at 190 mg/kg per day in 3 divided doses was given to
the mother which resulted in an fetal head circumference increase to the
76th percentile at 31 weeks' gestation. At birth, the girl's head
circumference was normal. Within 12 hours after birth, the serine
concentration in plasma dropped to a severely deficient value of 33
micromol/l, and serine was also depleted in cerebrospinal fluid. MRI was
normal, but EEG showed discrete seizure activity. After initiation of
L-serine treatment of 400 mg/kg per day, seizure activity diminished to
normal within 1 week. At 4 years of age the girl had normal growth and
psychomotor development, with follow-up MRI scans at 12 and 14 months
showing no brain abnormalities. Since the consanguineous couple had 2
severely affected children born with congenital microcephaly prior to
this child, de Koning et al. (2004) concluded that PHGDH deficiency is
an inborn metabolic error that can be successfully treated antenatally.

MOLECULAR GENETICS

To investigate the molecular basis of PHGDH deficiency, Klomp et al.
(2000) characterized the PHGDH mRNA sequence and analyzed it for
variations in 6 patients from 4 families with this disorder. Five
patients in 3 different families were homozygous for a single nucleotide
substitution predicted to change valine at position 490 to methionine
(606879.0001). The sixth patient was homozygous for a
valine-to-methionine substitution at position 425 (606879.0002). Both
mutations were located in the C terminus of the PHGDH gene. In vitro
expression of these mutant proteins resulted in significant reduction of
PHGDH enzyme activities. RNA blot analysis indicated abundant expression
of PHGDH in adult and fetal brain tissue. Taken together with the severe
neurologic impairment in these patients, the data suggested an important
role for PHGDH activity and L-serine biosynthesis in the metabolism,
development, and function of the central nervous system.

In 3 Dutch patients, including a brother and sister, and 2 unrelated
Turkish patients, who presented with congenital microcephaly,
psychomotor retardation, and seizures, Tabatabaie et al. (2009)
identified compound heterozygosity or homozygosity for 5 mutations in
the PHGDH gene, respectively (see, e.g., 606879.0003-606879.0006).
Studies in patient fibroblasts, transient overexpression in HEK293
cells, and molecular modeling onto the partial crystal structure of
3-PGDH suggested that missense mutations associated with 3-PGDH
deficiency, including the previously identified V490M and V425M
substitutions, either primarily affect substrate binding or result in
very low residual enzymatic activity.

*FIELD* RF
1. De Koning, T. J.; Duran, M.; Van Maldergem, L.; Pineda, M.; Dorland,
L.; Gooskens, R.; Jaeken, J.; Poll-The, B. T.: Congenital microcephaly
and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome
of treatment with amino acids. J. Inherit. Metab. Dis. 25: 119-125,
2002.

2. de Koning, T. J.; Klomp, L. W. J.; van Oppen, A. C. C.; Beemer,
F. A.; Dorland, L.; van den Berg, I. E. T.; Berger, R.: Prenatal
and early postnatal treatment in 3-phosphoglycerate-dehydrogenase
deficiency. (Letter) Lancet 364: 2221-2222, 2004.

3. Jaeken, J.; Detheux, M.; Van Maldergem, L.; Foulon, M.; Carchon,
H.; Van Schaftingen, E.: 3-Phosphoglycerate dehydrogenase deficiency:
an inborn error of serine biosynthesis. Arch. Dis. Child. 74: 542-545,
1996.

4. Klomp, L. W. J.; de Koning, T. J.; Malingre, H. E. M.; van Beurden,
E. A. C. M.; Brink, M.; Opdam, F. L.; Duran, M.; Jaeken, J.; Pineda,
M.; van Maldergem, L.; Poll-The, B. T.; van den Berg, I. E. T.; Berger,
R.: Molecular characterization of 3-phosphoglycerate dehydrogenase
deficiency--a neurometabolic disorder associated with reduced L-serine
biosynthesis. Am. J. Hum. Genet. 67: 1389-1399, 2000.

5. Tabatabaie, L.; de Koning, T. J.; Geboers, A. J. J. M.; van den
Berg, I. E. T.; Berger, R.; Klomp, L. W. J.: Novel mutations in 3-phosphoglycerate
dehydrogenase (PHGDH) are distributed throughout the protein and result
in altered enzyme kinetics. Hum. Mutat. 30: 749-756, 2009.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Growth retardation

HEAD AND NECK:
[Head];
Microcephaly, congenital;
[Eyes];
Cataracts, congenital;
Nystagmus

GENITOURINARY:
[Internal genitalia, male];
Small testes

SKELETAL:
[Hands];
Adducted thumbs

NEUROLOGIC:
[Central nervous system];
Mental retardation;
Seizures;
Dysmyelination;
Hypertonia;
Spastic quadriplegia;
Hypsarrhythmia or severe multifocal epileptic abnormalities with poor
background activity on EEG

HEMATOLOGY:
Megaloblastic anemia;
Thrombocytopenia

LABORATORY ABNORMALITIES:
Decrease plasma serine (fasting);
Decreased CSF serine;
Decreased PHGDH activity (fibroblasts);
Normal-to-decreased plasma glycine (fasting);
Decreased CSF glycine

MOLECULAR BASIS:
Caused by mutation in the phosphoglycerate dehydrogenase gene (PHGDH,
606879.0001)

*FIELD* CN
Kelly A. Przylepa - revised: 09/24/2008

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 09/24/2008

*FIELD* CN
Marla J. F. O'Neill - updated: 3/5/2010
Ada Hamosh - updated: 2/25/2005
Ada Hamosh - updated: 10/6/2003
Victor A. McKusick - updated: 12/12/2000

*FIELD* CD
Cynthia K. Ewing: 5/20/1997

*FIELD* ED
terry: 03/26/2012
carol: 5/4/2010
wwang: 3/8/2010
terry: 3/5/2010
wwang: 3/2/2005
terry: 2/25/2005
carol: 10/31/2003
cwells: 10/6/2003
carol: 4/24/2002
carol: 4/12/2002
mcapotos: 1/29/2001
mcapotos: 1/9/2001
mcapotos: 12/27/2000
terry: 12/12/2000
alopez: 11/17/1999
mark: 5/23/1997
mark: 5/20/1997

MIM 606879
*RECORD*
*FIELD* NO
606879
*FIELD* TI
*606879 PHOSPHOGLYCERATE DEHYDROGENASE; PHGDH
;;3-@PHOSPHOGLYCERATE DEHYDROGENASE; 3PGDH
read more*FIELD* TX

DESCRIPTION

3-Phosphoglycerate dehydrogenase (PHGDH; EC 1.1.1.95) catalyzes the
transition of 3-phosphoglycerate into 3-phosphohydroxypyruvate, which is
the first and rate-limiting step in the phosphorylated pathway of serine
biosynthesis, using NAD+/NADH as a cofactor.

CLONING

Cho et al. (2000) cloned a cDNA encoding phosphoglycerate dehydrogenase
from a human Jurkat T-cell cDNA library. The deduced 533-amino acid
protein, with a molecular mass of 56.8 kD, shares 94% sequence identity
with rat liver 3-PGDH. Northern blot analysis detected a major 2.1-kb
transcript at high levels in prostate, testis, ovary, brain, liver,
kidney, and pancreas and at low levels in thymus, colon, and heart. A
710-bp transcript appeared as a weaker band in most tissues in which the
2.1-kb mRNA was expressed, was more significant than the 2.1-kb mRNA in
heart, and was the only transcript present in skeletal muscle. The
2.1-kb transcript was also detected in most continuously growing tumor
cells tested.

GENE FUNCTION

Cho et al. (2000) found that TPA-induced monocytic differentiation of
U937 cells, which also resulted in growth arrest, abruptly downregulated
the expression of PHGDH. Removal of TPA restored cell growth through the
retrodifferentiation process and subsequent expression of PHGDH. These
findings suggested that the expression of PHGDH may be regulated at the
transcriptional level depending on tissue specificity and cellular
proliferative status.

Possemato et al. (2011) developed a method for identifying novel cancer
targets via negative-selection RNAi screening using a human breast
cancer xenograft model at an orthotopic site in the mouse. Using this
method, they screened a set of metabolic genes associated with
aggressive breast cancer and stemness to identify those required for in
vivo tumorigenesis. Among the genes identified, PHGDH is in a genomic
region of recurrent copy number gain in breast cancer and PHGDH protein
levels are elevated in 70% of estrogen receptor-negative breast cancers.
PHGDH catalyzes the first step in the serine biosynthesis pathway, and
breast cancer cells with high PHGDH expression have increased serine
synthesis flux. Suppression of PHGDH in cell lines with elevated PHGDH
expression, but not in those without, caused a strong decrease in cell
proliferation and a reduction in serine synthesis. Possemato et al.
(2011) found that PHGDH suppression does not affect intracellular serine
levels, but causes a drop in levels of alpha-ketoglutarate, another
output of the pathway and a tricarboxylic acid (TCA) cycle intermediate.
In cells with high PHGDH expression, the serine synthesis pathway
contributes approximately 50% of the total anaplerotic flux of glutamine
into the TCA cycle. Possemato et al. (2011) concluded that certain
breast cancers are dependent on increased serine pathway flux caused by
PHGDH overexpression.

Locasale et al. (2011) found that in some cancer cells a relatively
large amount of glycolytic carbon is diverted into serine and glycine
metabolism through PHGDH. An analysis of human cancers showed that PHGDH
is recurrently amplified in a genomic region of focal number copy gain
most commonly found in melanoma. Decreasing PHGDH expression impaired
proliferation in amplified cell lines. Increased expression was also
associated with breast cancer subtypes, and ectopic expression of PHGDH
in mammary epithelial cells disrupted acinar morphogenesis and induced
other phenotypic alterations that may predispose cells to
transformation. Locasale et al. (2011) concluded that the diversion of
glycolytic flux into a specific alternate pathway can be selected during
tumor development and may contribute to the pathogenesis of human
cancer.

MAPPING

By fluorescence in situ hybridization, Baek et al. (2000) mapped the
PHGDH gene to chromosome 1p12. However, using 2 radiation hybrid panels,
Klomp et al. (2000) mapped the PHGDH gene to 1q12.

MOLECULAR GENETICS

To investigate the molecular basis of phosphoglycerate dehydrogenase
deficiency (601815), Klomp et al. (2000) characterized the PHGDH mRNA
sequence and analyzed it for variations in 6 patients from 4 families
with this disorder. Five patients in 3 different families were
homozygous for a single nucleotide substitution predicted to change
valine at position 490 to methionine (V490M; 606879.0001). The sixth
patient was homozygous for a valine-to-methionine substitution at
position 425 (V425M; 606879.0002). Both mutations were located in the C
terminus of the PHGDH gene. In vitro expression of these mutant proteins
resulted in significant reduction of PHGDH enzyme activities. RNA blot
analysis indicated abundant expression of PHGDH in adult and fetal brain
tissue. Taken together with the severe neurologic impairment in these
patients, the data suggested an important role for PHGDH activity and
L-serine biosynthesis in the metabolism, development, and function of
the central nervous system.

Tabatabaie et al. (2009) identified 1 frameshift and 4 missense
mutations in the PHGDH gene in 5 patients with phosphoglycerate
dehydrogenase deficiency (see, e.g., 606879.0003-606879.0006). Studies
in patient fibroblasts showed significant, but incomplete, reduction
with missense mutations, including the previously identified V490M and
V425M substitutions. Transient overexpression studies in HEK293 cells
and molecular modeling onto the partial crystal structure of 3-PGDH
suggested that missense mutations associated with 3-PGDH deficiency
either primarily affect substrate binding or result in very low residual
enzymatic activity.

*FIELD* AV
.0001
PHOSPHOGLYCERATE DEHYDROGENASE DEFICIENCY
PHGDH, VAL490MET

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
PHGDH, VAL425MET

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
PHGDH, 1-BP DEL, 712G

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
PHGDH, ARG135TRP

See 606879.0003 and Tabatabaie et al. (2009).

.0005
PHOSPHOGLYCERATE DEHYDROGENASE DEFICIENCY
PHGDH, GLY377SER

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
PHGDH, VAL261MET

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.

*FIELD* RF
1. Baek, J. Y.; Jun, D. Y.; Taub, D.; Kim, Y. H.: Assignment of human
3-phosphoglycerate dehydrogenase (PHGDH) to human chromosome band
1p12 by fluorescence in situ hybridization. Cytogenet. Cell Genet. 89:
6-7, 2000.

2. Cho, H. M.; Jun, D. Y.; Bae, M. A.; Ahn, J. D.; Kim, Y. H.: Nucleotide
sequence and differential expression of the human 3-phosphoglycerate
dehydrogenase gene. Gene 245: 193-201, 2000.

3. Klomp, L. W. J.; de Koning, T. J.; Malingre, H. E. M.; van Beurden,
E. A. C. M.; Brink, M.; Opdam, F. L.; Duran, M.; Jaeken, J.; Pineda,
M.; van Maldergem, L.; Poll-The, B. T.; van den Berg, I. E. T.; Berger,
R.: Molecular characterization of 3-phosphoglycerate dehydrogenase
deficiency--a neurometabolic disorder associated with reduced L-serine
biosynthesis. Am. J. Hum. Genet. 67: 1389-1399, 2000.

4. Locasale, J. W.; Grassian, A. R.; Melman, T.; Lyssiotis, C. A.;
Mattaini, K. R.; Bass, A. J.; Heffron, G.; Metallo, C. M.; Muranen,
T.; Sharfi, H.; Sasaki, A. T.; Anastasiou, D.; and 14 others: Phosphoglycerate
dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nature
Genet. 43: 869-874, 2011.

5. Pineda, M.; Vilaseca, M. A.; Artuch, R.; Santos, S.; Garcia Gonzales,
M. M.; Sau, I.; Aracil, A.; Van Schaftingen, E.; Jaeken, J.: 3-Phosphoglycerate
dehydrogenase deficiency in a patient with West syndrome. Dev. Med.
Child Neurol. 42: 629-633, 2000.

6. Possemato, R.; Marks, K. M.; Shaul, Y. D.; Pacold, M. E.; Kim,
D.; Birsoy, K.; Sethumadhavan, S.; Woo, H.-K.; Jang, H. G.; Jha, A.
K.; Chen, W. W.; Barrett, F. G.; and 15 others: Functional genomics
reveal that the serine synthesis pathway is essential in breast cancer. Nature 476:
346-350, 2011.

7. Tabatabaie, L.; de Koning, T. J.; Geboers, A. J. J. M.; van den
Berg, I. E. T.; Berger, R.; Klomp, L. W. J.: Novel mutations in 3-phosphoglycerate
dehydrogenase (PHGDH) are distributed throughout the protein and result
in altered enzyme kinetics. Hum. Mutat. 30: 749-756, 2009.

*FIELD* CN
Ada Hamosh - updated: 10/7/2011
Ada Hamosh - updated: 9/6/2011
Marla J. F. O'Neill - updated: 3/5/2010
Ada Hamosh - updated: 10/6/2003

*FIELD* CD
Carol A. Bocchini: 4/24/2002

*FIELD* ED
alopez: 10/13/2011
terry: 10/7/2011
alopez: 9/7/2011
terry: 9/6/2011
wwang: 3/8/2010
terry: 3/5/2010
wwang: 3/2/2005
carol: 10/31/2003
cwells: 10/6/2003
mgross: 4/25/2002
carol: 4/24/2002