Full text data of PNPO
PNPO
[Confidence: low (only semi-automatic identification from reviews)]
Pyridoxine-5'-phosphate oxidase; 1.4.3.5 (Pyridoxamine-phosphate oxidase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Pyridoxine-5'-phosphate oxidase; 1.4.3.5 (Pyridoxamine-phosphate oxidase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q9NVS9
ID PNPO_HUMAN Reviewed; 261 AA.
AC Q9NVS9; D3DTT9;
DT 26-SEP-2003, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-2000, sequence version 1.
DT 22-JAN-2014, entry version 126.
DE RecName: Full=Pyridoxine-5'-phosphate oxidase;
DE EC=1.4.3.5;
DE AltName: Full=Pyridoxamine-phosphate oxidase;
GN Name=PNPO;
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].
RC TISSUE=Brain;
RA Kwon O.-S.;
RL Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Teratocarcinoma;
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 [3]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lymph;
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 [5]
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 [6]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 49-161 IN COMPLEX WITH FMN
RP AND PYRIDOXAL 5'-PHOSPHATE, PARTIAL PROTEIN SEQUENCE, SUBUNIT, ENZYME
RP REGULATION, AND FUNCTION.
RX PubMed=12824491; DOI=10.1110/ps.0356203;
RA Musayev F.N., Di Salvo M.L., Ko T.-P., Schirch V., Safo M.K.;
RT "Structure and properties of recombinant human pyridoxine 5'-phosphate
RT oxidase.";
RL Protein Sci. 12:1455-1463(2003).
RN [7]
RP VARIANT PNPO DEFICIENCY TRP-229, AND VARIANT LYS-50.
RX PubMed=15772097; DOI=10.1093/hmg/ddi120;
RA Mills P.B., Surtees R.A.H., Champion M.P., Beesley C.E., Dalton N.,
RA Scambler P.J., Heales S.J.R., Briddon A., Scheimberg I.,
RA Hoffmann G.F., Zschocke J., Clayton P.T.;
RT "Neonatal epileptic encephalopathy caused by mutations in the PNPO
RT gene encoding pyridox(am)ine 5'-phosphate oxidase.";
RL Hum. Mol. Genet. 14:1077-1086(2005).
CC -!- FUNCTION: Catalyzes the oxidation of either pyridoxine 5'-
CC phosphate (PNP) or pyridoxamine 5'-phosphate (PMP) into pyridoxal
CC 5'-phosphate (PLP).
CC -!- CATALYTIC ACTIVITY: Pyridoxamine 5'-phosphate + H(2)O + O(2) =
CC pyridoxal 5'-phosphate + NH(3) + H(2)O(2).
CC -!- CATALYTIC ACTIVITY: Pyridoxine 5'-phosphate + O(2) = pyridoxal 5'-
CC phosphate + H(2)O(2).
CC -!- COFACTOR: Binds 1 FMN per subunit.
CC -!- PATHWAY: Cofactor biosynthesis; B6 vitamer interconversion;
CC pyridoxal 5'-phosphate from pyridoxamine 5'-phosphate: step 1/1.
CC -!- PATHWAY: Cofactor biosynthesis; B6 vitamer interconversion;
CC pyridoxal 5'-phosphate from pyridoxine 5'-phosphate: step 1/1.
CC -!- SUBUNIT: Homodimer.
CC -!- DISEASE: Pyridoxine-5'-phosphate oxidase deficiency (PNPO
CC deficiency) [MIM:610090]: The main feature of neonatal epileptic
CC encephalopathy is the onset within hours of birth of a severe
CC seizure disorder that does not respond to anticonvulsant drugs and
CC can be fatal. Seizures can cease with the administration of PLP,
CC being resistant to treatment with pyridoxine,. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the pyridoxamine 5'-phosphate oxidase
CC family.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF468030; AAM76918.1; -; mRNA.
DR EMBL; AK001397; BAA91668.1; -; mRNA.
DR EMBL; CH471109; EAW94770.1; -; Genomic_DNA.
DR EMBL; CH471109; EAW94771.1; -; Genomic_DNA.
DR EMBL; BC006525; AAH06525.1; -; mRNA.
DR RefSeq; NP_060599.1; NM_018129.3.
DR UniGene; Hs.631742; -.
DR PDB; 1NRG; X-ray; 1.95 A; A=1-261.
DR PDB; 3HY8; X-ray; 2.50 A; A=1-261.
DR PDBsum; 1NRG; -.
DR PDBsum; 3HY8; -.
DR DisProt; DP00168; -.
DR ProteinModelPortal; Q9NVS9; -.
DR SMR; Q9NVS9; 49-261.
DR STRING; 9606.ENSP00000225573; -.
DR DrugBank; DB00114; Pyridoxal Phosphate.
DR PhosphoSite; Q9NVS9; -.
DR DMDM; 37082126; -.
DR REPRODUCTION-2DPAGE; IPI00018272; -.
DR PaxDb; Q9NVS9; -.
DR PeptideAtlas; Q9NVS9; -.
DR PRIDE; Q9NVS9; -.
DR Ensembl; ENST00000225573; ENSP00000225573; ENSG00000108439.
DR GeneID; 55163; -.
DR KEGG; hsa:55163; -.
DR UCSC; uc002imo.3; human.
DR CTD; 55163; -.
DR GeneCards; GC17P046018; -.
DR HGNC; HGNC:30260; PNPO.
DR HPA; HPA023204; -.
DR HPA; HPA027776; -.
DR MIM; 603287; gene.
DR MIM; 610090; phenotype.
DR neXtProt; NX_Q9NVS9; -.
DR Orphanet; 79096; Pyridoxal phosphate-responsive seizures.
DR PharmGKB; PA134915565; -.
DR eggNOG; COG0259; -.
DR HOGENOM; HOG000242755; -.
DR HOVERGEN; HBG045634; -.
DR InParanoid; Q9NVS9; -.
DR KO; K00275; -.
DR OMA; PEHWGGY; -.
DR PhylomeDB; Q9NVS9; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR SABIO-RK; Q9NVS9; -.
DR UniPathway; UPA00190; UER00304.
DR UniPathway; UPA00190; UER00305.
DR ChiTaRS; PNPO; human.
DR EvolutionaryTrace; Q9NVS9; -.
DR GeneWiki; PNPO; -.
DR GenomeRNAi; 55163; -.
DR NextBio; 58925; -.
DR PRO; PR:Q9NVS9; -.
DR ArrayExpress; Q9NVS9; -.
DR Bgee; Q9NVS9; -.
DR CleanEx; HS_PNPO; -.
DR Genevestigator; Q9NVS9; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0010181; F:FMN binding; IEA:InterPro.
DR GO; GO:0004733; F:pyridoxamine-phosphate oxidase activity; TAS:Reactome.
DR GO; GO:0008615; P:pyridoxine biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0042816; P:vitamin B6 metabolic process; TAS:Reactome.
DR Gene3D; 2.30.110.10; -; 1.
DR InterPro; IPR000659; Pyridox_Oxase.
DR InterPro; IPR019740; Pyridox_Oxase_CS.
DR InterPro; IPR011576; Pyridox_Oxase_FMN-bd.
DR InterPro; IPR019576; Pyridoxamine_oxidase_dimer_C.
DR InterPro; IPR012349; Split_barrel_FMN-bd.
DR PANTHER; PTHR10851; PTHR10851; 1.
DR Pfam; PF10590; PNPOx_C; 1.
DR Pfam; PF01243; Pyridox_oxidase; 1.
DR PIRSF; PIRSF000190; Pyd_amn-ph_oxd; 1.
DR SUPFAM; SSF50475; SSF50475; 1.
DR TIGRFAMs; TIGR00558; pdxH; 1.
DR PROSITE; PS01064; PYRIDOX_OXIDASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Direct protein sequencing;
KW Disease mutation; Epilepsy; Flavoprotein; FMN; Oxidoreductase;
KW Polymorphism; Pyridoxal phosphate; Pyridoxine biosynthesis;
KW Reference proteome.
FT CHAIN 1 261 Pyridoxine-5'-phosphate oxidase.
FT /FTId=PRO_0000167783.
FT NP_BIND 110 111 FMN.
FT NP_BIND 174 175 FMN.
FT REGION 225 227 Substrate binding.
FT BINDING 95 95 FMN.
FT BINDING 98 98 FMN; via amide nitrogen.
FT BINDING 100 100 Substrate.
FT BINDING 117 117 FMN.
FT BINDING 157 157 Substrate.
FT BINDING 161 161 Substrate.
FT BINDING 165 165 Substrate.
FT VARIANT 50 50 E -> K.
FT /FTId=VAR_029358.
FT VARIANT 116 116 R -> Q (in dbSNP:rs17679445).
FT /FTId=VAR_029359.
FT VARIANT 229 229 R -> W (in PNPO deficiency; strong
FT activity decrease; dbSNP:rs104894629).
FT /FTId=VAR_029360.
FT HELIX 58 71
FT STRAND 80 86
FT STRAND 88 90
FT STRAND 92 98
FT STRAND 102 105
FT STRAND 106 112
FT HELIX 116 123
FT STRAND 126 133
FT HELIX 134 136
FT STRAND 138 148
FT HELIX 151 160
FT HELIX 163 171
FT HELIX 181 194
FT TURN 195 197
FT STRAND 206 211
FT STRAND 214 220
FT STRAND 228 234
FT STRAND 254 258
SQ SEQUENCE 261 AA; 29988 MW; 2C74E9F962FE2A95 CRC64;
MTCWLRGVTA TFGRPAEWPG YLSHLCGRSA AMDLGPMRKS YRGDREAFEE THLTSLDPVK
QFAAWFEEAV QCPDIGEANA MCLATCTRDG KPSARMLLLK GFGKDGFRFF TNFESRKGKE
LDSNPFASLV FYWEPLNRQV RVEGPVKKLP EEEAECYFHS RPKSSQIGAV VSHQSSVIPD
REYLRKKNEE LEQLYQDQEV PKPKSWGGYV LYPQVMEFWQ GQTNRLHDRI VFRRGLPTGD
SPLGPMTHRG EEDWLYERLA P
//
ID PNPO_HUMAN Reviewed; 261 AA.
AC Q9NVS9; D3DTT9;
DT 26-SEP-2003, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-2000, sequence version 1.
DT 22-JAN-2014, entry version 126.
DE RecName: Full=Pyridoxine-5'-phosphate oxidase;
DE EC=1.4.3.5;
DE AltName: Full=Pyridoxamine-phosphate oxidase;
GN Name=PNPO;
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].
RC TISSUE=Brain;
RA Kwon O.-S.;
RL Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Teratocarcinoma;
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 [3]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lymph;
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 [5]
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 [6]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 49-161 IN COMPLEX WITH FMN
RP AND PYRIDOXAL 5'-PHOSPHATE, PARTIAL PROTEIN SEQUENCE, SUBUNIT, ENZYME
RP REGULATION, AND FUNCTION.
RX PubMed=12824491; DOI=10.1110/ps.0356203;
RA Musayev F.N., Di Salvo M.L., Ko T.-P., Schirch V., Safo M.K.;
RT "Structure and properties of recombinant human pyridoxine 5'-phosphate
RT oxidase.";
RL Protein Sci. 12:1455-1463(2003).
RN [7]
RP VARIANT PNPO DEFICIENCY TRP-229, AND VARIANT LYS-50.
RX PubMed=15772097; DOI=10.1093/hmg/ddi120;
RA Mills P.B., Surtees R.A.H., Champion M.P., Beesley C.E., Dalton N.,
RA Scambler P.J., Heales S.J.R., Briddon A., Scheimberg I.,
RA Hoffmann G.F., Zschocke J., Clayton P.T.;
RT "Neonatal epileptic encephalopathy caused by mutations in the PNPO
RT gene encoding pyridox(am)ine 5'-phosphate oxidase.";
RL Hum. Mol. Genet. 14:1077-1086(2005).
CC -!- FUNCTION: Catalyzes the oxidation of either pyridoxine 5'-
CC phosphate (PNP) or pyridoxamine 5'-phosphate (PMP) into pyridoxal
CC 5'-phosphate (PLP).
CC -!- CATALYTIC ACTIVITY: Pyridoxamine 5'-phosphate + H(2)O + O(2) =
CC pyridoxal 5'-phosphate + NH(3) + H(2)O(2).
CC -!- CATALYTIC ACTIVITY: Pyridoxine 5'-phosphate + O(2) = pyridoxal 5'-
CC phosphate + H(2)O(2).
CC -!- COFACTOR: Binds 1 FMN per subunit.
CC -!- PATHWAY: Cofactor biosynthesis; B6 vitamer interconversion;
CC pyridoxal 5'-phosphate from pyridoxamine 5'-phosphate: step 1/1.
CC -!- PATHWAY: Cofactor biosynthesis; B6 vitamer interconversion;
CC pyridoxal 5'-phosphate from pyridoxine 5'-phosphate: step 1/1.
CC -!- SUBUNIT: Homodimer.
CC -!- DISEASE: Pyridoxine-5'-phosphate oxidase deficiency (PNPO
CC deficiency) [MIM:610090]: The main feature of neonatal epileptic
CC encephalopathy is the onset within hours of birth of a severe
CC seizure disorder that does not respond to anticonvulsant drugs and
CC can be fatal. Seizures can cease with the administration of PLP,
CC being resistant to treatment with pyridoxine,. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the pyridoxamine 5'-phosphate oxidase
CC family.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF468030; AAM76918.1; -; mRNA.
DR EMBL; AK001397; BAA91668.1; -; mRNA.
DR EMBL; CH471109; EAW94770.1; -; Genomic_DNA.
DR EMBL; CH471109; EAW94771.1; -; Genomic_DNA.
DR EMBL; BC006525; AAH06525.1; -; mRNA.
DR RefSeq; NP_060599.1; NM_018129.3.
DR UniGene; Hs.631742; -.
DR PDB; 1NRG; X-ray; 1.95 A; A=1-261.
DR PDB; 3HY8; X-ray; 2.50 A; A=1-261.
DR PDBsum; 1NRG; -.
DR PDBsum; 3HY8; -.
DR DisProt; DP00168; -.
DR ProteinModelPortal; Q9NVS9; -.
DR SMR; Q9NVS9; 49-261.
DR STRING; 9606.ENSP00000225573; -.
DR DrugBank; DB00114; Pyridoxal Phosphate.
DR PhosphoSite; Q9NVS9; -.
DR DMDM; 37082126; -.
DR REPRODUCTION-2DPAGE; IPI00018272; -.
DR PaxDb; Q9NVS9; -.
DR PeptideAtlas; Q9NVS9; -.
DR PRIDE; Q9NVS9; -.
DR Ensembl; ENST00000225573; ENSP00000225573; ENSG00000108439.
DR GeneID; 55163; -.
DR KEGG; hsa:55163; -.
DR UCSC; uc002imo.3; human.
DR CTD; 55163; -.
DR GeneCards; GC17P046018; -.
DR HGNC; HGNC:30260; PNPO.
DR HPA; HPA023204; -.
DR HPA; HPA027776; -.
DR MIM; 603287; gene.
DR MIM; 610090; phenotype.
DR neXtProt; NX_Q9NVS9; -.
DR Orphanet; 79096; Pyridoxal phosphate-responsive seizures.
DR PharmGKB; PA134915565; -.
DR eggNOG; COG0259; -.
DR HOGENOM; HOG000242755; -.
DR HOVERGEN; HBG045634; -.
DR InParanoid; Q9NVS9; -.
DR KO; K00275; -.
DR OMA; PEHWGGY; -.
DR PhylomeDB; Q9NVS9; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR SABIO-RK; Q9NVS9; -.
DR UniPathway; UPA00190; UER00304.
DR UniPathway; UPA00190; UER00305.
DR ChiTaRS; PNPO; human.
DR EvolutionaryTrace; Q9NVS9; -.
DR GeneWiki; PNPO; -.
DR GenomeRNAi; 55163; -.
DR NextBio; 58925; -.
DR PRO; PR:Q9NVS9; -.
DR ArrayExpress; Q9NVS9; -.
DR Bgee; Q9NVS9; -.
DR CleanEx; HS_PNPO; -.
DR Genevestigator; Q9NVS9; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0010181; F:FMN binding; IEA:InterPro.
DR GO; GO:0004733; F:pyridoxamine-phosphate oxidase activity; TAS:Reactome.
DR GO; GO:0008615; P:pyridoxine biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0042816; P:vitamin B6 metabolic process; TAS:Reactome.
DR Gene3D; 2.30.110.10; -; 1.
DR InterPro; IPR000659; Pyridox_Oxase.
DR InterPro; IPR019740; Pyridox_Oxase_CS.
DR InterPro; IPR011576; Pyridox_Oxase_FMN-bd.
DR InterPro; IPR019576; Pyridoxamine_oxidase_dimer_C.
DR InterPro; IPR012349; Split_barrel_FMN-bd.
DR PANTHER; PTHR10851; PTHR10851; 1.
DR Pfam; PF10590; PNPOx_C; 1.
DR Pfam; PF01243; Pyridox_oxidase; 1.
DR PIRSF; PIRSF000190; Pyd_amn-ph_oxd; 1.
DR SUPFAM; SSF50475; SSF50475; 1.
DR TIGRFAMs; TIGR00558; pdxH; 1.
DR PROSITE; PS01064; PYRIDOX_OXIDASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Direct protein sequencing;
KW Disease mutation; Epilepsy; Flavoprotein; FMN; Oxidoreductase;
KW Polymorphism; Pyridoxal phosphate; Pyridoxine biosynthesis;
KW Reference proteome.
FT CHAIN 1 261 Pyridoxine-5'-phosphate oxidase.
FT /FTId=PRO_0000167783.
FT NP_BIND 110 111 FMN.
FT NP_BIND 174 175 FMN.
FT REGION 225 227 Substrate binding.
FT BINDING 95 95 FMN.
FT BINDING 98 98 FMN; via amide nitrogen.
FT BINDING 100 100 Substrate.
FT BINDING 117 117 FMN.
FT BINDING 157 157 Substrate.
FT BINDING 161 161 Substrate.
FT BINDING 165 165 Substrate.
FT VARIANT 50 50 E -> K.
FT /FTId=VAR_029358.
FT VARIANT 116 116 R -> Q (in dbSNP:rs17679445).
FT /FTId=VAR_029359.
FT VARIANT 229 229 R -> W (in PNPO deficiency; strong
FT activity decrease; dbSNP:rs104894629).
FT /FTId=VAR_029360.
FT HELIX 58 71
FT STRAND 80 86
FT STRAND 88 90
FT STRAND 92 98
FT STRAND 102 105
FT STRAND 106 112
FT HELIX 116 123
FT STRAND 126 133
FT HELIX 134 136
FT STRAND 138 148
FT HELIX 151 160
FT HELIX 163 171
FT HELIX 181 194
FT TURN 195 197
FT STRAND 206 211
FT STRAND 214 220
FT STRAND 228 234
FT STRAND 254 258
SQ SEQUENCE 261 AA; 29988 MW; 2C74E9F962FE2A95 CRC64;
MTCWLRGVTA TFGRPAEWPG YLSHLCGRSA AMDLGPMRKS YRGDREAFEE THLTSLDPVK
QFAAWFEEAV QCPDIGEANA MCLATCTRDG KPSARMLLLK GFGKDGFRFF TNFESRKGKE
LDSNPFASLV FYWEPLNRQV RVEGPVKKLP EEEAECYFHS RPKSSQIGAV VSHQSSVIPD
REYLRKKNEE LEQLYQDQEV PKPKSWGGYV LYPQVMEFWQ GQTNRLHDRI VFRRGLPTGD
SPLGPMTHRG EEDWLYERLA P
//
MIM
603287
*RECORD*
*FIELD* NO
603287
*FIELD* TI
*603287 PYRIDOXAMINE 5-PRIME-PHOSPHATE OXIDASE; PNPO
;;PYRIDOXAMINE-PHOSPHATE OXIDASE
read more*FIELD* TX
DESCRIPTION
Vitamin B6, or pyridoxal 5-prime-phosphate (PLP), is critical for normal
cellular function, and some cancer cells have notable differences in
vitamin B6 metabolism compared to their normal counterparts. The
rate-limiting enzyme in vitamin B6 synthesis is
pyridoxine-5-prime-phosphate (PNP) oxidase (PNPO; EC 1.4.3.5).
CLONING
Ngo et al. (1998) isolated a PNPO clone from a rat liver library. They
found that the predicted 30-kD protein contained the PNPO signature
motif found in the PNPO of S. cerevisiae and bacteria and 5 predicted
protein kinase C (see 176960) phosphorylation sites.
Kang et al. (2004) cloned full-length PNPO from a whole brain cDNA
library. The deduced 261-amino acid protein has a calculated molecular
mass of 30 kD. Posttranslational modification sites include a sulfation
site, 9 phosphorylation sites, 3 N-myristoylation sites, and an RGD cell
attachment sequence. PNPO shares 90% amino acid identity with mouse
Pnpo. Northern blot analysis detected transcripts of 2.4 and 3.4 kb in
all human tissues examined, with the difference in transcript size due
to use of alternative polyadenylation sites. Highest expression was in
liver, followed by skeletal muscle and kidney. Western blot analysis
detected a 30-kD protein in all tissues and cell lines examined.
GENE FUNCTION
PNPO activity is developmentally regulated in rat liver, being low in
fetal liver and high in adult liver. Ngo et al. (1998) showed that PNPO
expression was similarly developmentally regulated in rat brain.
Additionally, Ngo et al. (1998) demonstrated that, analogous to rodent
hepatomas, PNPO expression in rodent brain tumors was comparable to or
lower than that present in fetal rat brain. However, the human
neuroblastoma cell lines examined displayed variable PNPO activity; a
human hepatocellular carcinoma cell line contained relatively high PNPO
activity, comparable to that found in normal human liver.
Kang et al. (2004) characterized the enzymatic properties of recombinant
PNPO following expression in E. coli. PNPO converted both PNP and
pyridoxamine 5-prime-phosphate to PLP, and the PLP product was an
inhibitor. Mutation analysis indicated that the first N-terminal
conserved helix segment and the C-terminal 25 residues were required for
enzymatic activity.
GENE STRUCTURE
Kang et al. (2004) determined that the PNPO gene contains 7 exons and
spans 7.7 kb. The promoter region shows characteristics of housekeeping
genes, with a CpG island and Sp1 (189906)-binding sites, but no
TATA-like sequences.
MAPPING
By genomic sequence analysis, Kang et al. (2004) mapped the PNPO gene to
chromosome 17q21.32. They mapped the mouse gene to chromosome 11.
MOLECULAR GENETICS
In 5 patients from 3 families with PNPO deficiency (610090), Mills et
al. (2005) identified homozygous missense, splice site, and stop codon
mutations in the PNPO gene. Expression studies in Chinese hamster ovary
cells showed that the splice site (IVS3-1G-A; 603287.0002) and stop
codon (X262Q; 603287.0003) mutations were null activity mutations and
that the missense mutation (R229W; 603287.0001) markedly reduced
pyridox(am)ine phosphate oxidase activity. The authors suggested that
maintenance of optimal PLP levels in the brain may be important in many
neurologic disorders in which neurotransmitter metabolism is disturbed
(either as a primary or as a secondary phenomenon).
*FIELD* AV
.0001
PYRIDOXAMINE 5-PRIME-PHOSPHATE OXIDASE DEFICIENCY
PNPO, ARG229TRP
In twin boys, the children of consanguineous Turkish parents, with PNPO
deficiency (610090), Mills et al. (2005) detected a homozygous C-to-T
transition in exon 7 of the PNPO gene, resulting in a substitution of
tryptophan for the conserved arginine-229 residue (R229W). At least 4
and possibly 6 sibs from this family, including the twins, died from the
same disorder. Brautigam et al. (2002) had described the clinical and
laboratory findings in these patients.
.0002
PYRIDOXAMINE 5-PRIME-PHOSPHATE OXIDASE DEFICIENCY
PNPO, IVS3, G-A, -1
In an infant with PNPO deficiency (610090), Mills et al. (2005) found a
splice mutation in intron 3 (IVS3-1G-A) on 1 allele of the PNPO gene.
The missense mutation carried by the other allele was considered to be a
polymorphism. The parents were second cousins of East African Asian
origin. Patient fibroblast mRNA lacked exon 4, confirming aberrant
splicing. This patient was the only one studied by Mills et al. (2005)
to receive PLP treatment and to survive beyond the neonatal period, but
showed persistent central hypotonia and painful dystonic spasms as well
as some seizures by the second year of life. He had marked acquired
microcephaly and moderate to severe developmental delay.
.0003
PYRIDOXAMINE 5-PRIME-PHOSPHATE OXIDASE DEFICIENCY
PNPO, TER262GLN
In 2 affected sibs from a consanguineous Pakistani family with PNPO
deficiency (610090), Mills et al. (2005) detected a homozygous T-to-C
transition in exon 7 of the PNPO gene that resulted in substitution of
glutamine for the stop codon at position 262 (X262Q) and the addition of
28 amino acids. Expression studies demonstrated that X262Q PNPO is a
null activity mutant.
.0004
PYRIDOXAMINE 5-PRIME-PHOSPHATE OXIDASE DEFICIENCY
PNPO, ALA174TER
In a male infant with PNPO deficiency (610090), Ruiz et al. (2008)
identified a homozygous 520C-T transition in exon 5 of the PNPO gene,
resulting in an ala174-to-ter (A174X) substitution. The patient had
severe seizures and myoclonus within the first hours of life and died at
age 48 days.
*FIELD* RF
1. Brautigam, C.; Hyland, K.; Wevers, R.; Sharma, R.; Wagner, L.;
Stock, G.-J.; Heitmann, F.; Hoffmann, G. F.: Clinical and laboratory
findings in twins with neonatal epileptic encephalopathy mimicking
aromatic L-amino acid decarboxylase deficiency. Neuropediatrics 33:
113-117, 2002.
2. Kang, J. H.; Hong, M.-L.; Kim, D. W.; Park, J.; Kang, T.-C.; Won,
M. H.; Baek, N.-I.; Moon, B. J.; Choi, S. Y.; Kwon, O.-S.: Genomic
organization, tissue distribution and deletion mutation of human pyridoxine
5-prime-phosphate oxidase. Europ. J. Biochem. 271: 2452-2461, 2004.
3. Mills, P. B.; Surtees, R. A. H.; Champion, M. P.; Beesley, C. E.;
Dalton, N.; Scambler, P. J.; Heales, S. J. R.; Briddon, A.; Schmeimberg,
I.; Hoffmann, G. F.; Zschocke, J.; Clayton, P. T.: Neonatal epileptic
encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine
5-prime-phosphate oxidase. Hum. Molec. Genet. 14: 1077-1086, 2005.
4. Ngo, E. O.; LePage, G. R.; Thanassi, J. W.; Meisler, N.; Nutter,
L. M.: Absence of pyridoxine-5-prime-phosphate oxidase (PNPO) activity
in neoplastic cells: isolation, characterization, and expression of
PNPO cDNA. Biochemistry 37: 7741-7748, 1998.
5. Ruiz, A.; Garcia-Villoria, J.; Ormazabal, A.; Zschocke, J.; Fiol,
M.; Navarro-Sastre, A.; Artuch, R.; Vilaseca, M. A.; Ribes, A.: A
new fatal case of pyridox(am)ine 5-prime-phosphate oxidase (PNPO)
deficiency. Molec. Genet. Metab. 93: 216-218, 2008.
*FIELD* CN
Cassandra L. Kniffin - updated: 3/3/2008
George E. Tiller - updated: 5/8/2006
Patricia A. Hartz - updated: 8/16/2004
*FIELD* CD
Jennifer P. Macke: 11/13/1998
*FIELD* ED
wwang: 03/03/2008
ckniffin: 3/3/2008
alopez: 5/16/2006
alopez: 5/9/2006
alopez: 5/8/2006
alopez: 1/20/2006
mgross: 9/8/2004
terry: 8/16/2004
carol: 8/5/2004
alopez: 1/11/1999
alopez: 11/13/1998
*RECORD*
*FIELD* NO
603287
*FIELD* TI
*603287 PYRIDOXAMINE 5-PRIME-PHOSPHATE OXIDASE; PNPO
;;PYRIDOXAMINE-PHOSPHATE OXIDASE
read more*FIELD* TX
DESCRIPTION
Vitamin B6, or pyridoxal 5-prime-phosphate (PLP), is critical for normal
cellular function, and some cancer cells have notable differences in
vitamin B6 metabolism compared to their normal counterparts. The
rate-limiting enzyme in vitamin B6 synthesis is
pyridoxine-5-prime-phosphate (PNP) oxidase (PNPO; EC 1.4.3.5).
CLONING
Ngo et al. (1998) isolated a PNPO clone from a rat liver library. They
found that the predicted 30-kD protein contained the PNPO signature
motif found in the PNPO of S. cerevisiae and bacteria and 5 predicted
protein kinase C (see 176960) phosphorylation sites.
Kang et al. (2004) cloned full-length PNPO from a whole brain cDNA
library. The deduced 261-amino acid protein has a calculated molecular
mass of 30 kD. Posttranslational modification sites include a sulfation
site, 9 phosphorylation sites, 3 N-myristoylation sites, and an RGD cell
attachment sequence. PNPO shares 90% amino acid identity with mouse
Pnpo. Northern blot analysis detected transcripts of 2.4 and 3.4 kb in
all human tissues examined, with the difference in transcript size due
to use of alternative polyadenylation sites. Highest expression was in
liver, followed by skeletal muscle and kidney. Western blot analysis
detected a 30-kD protein in all tissues and cell lines examined.
GENE FUNCTION
PNPO activity is developmentally regulated in rat liver, being low in
fetal liver and high in adult liver. Ngo et al. (1998) showed that PNPO
expression was similarly developmentally regulated in rat brain.
Additionally, Ngo et al. (1998) demonstrated that, analogous to rodent
hepatomas, PNPO expression in rodent brain tumors was comparable to or
lower than that present in fetal rat brain. However, the human
neuroblastoma cell lines examined displayed variable PNPO activity; a
human hepatocellular carcinoma cell line contained relatively high PNPO
activity, comparable to that found in normal human liver.
Kang et al. (2004) characterized the enzymatic properties of recombinant
PNPO following expression in E. coli. PNPO converted both PNP and
pyridoxamine 5-prime-phosphate to PLP, and the PLP product was an
inhibitor. Mutation analysis indicated that the first N-terminal
conserved helix segment and the C-terminal 25 residues were required for
enzymatic activity.
GENE STRUCTURE
Kang et al. (2004) determined that the PNPO gene contains 7 exons and
spans 7.7 kb. The promoter region shows characteristics of housekeeping
genes, with a CpG island and Sp1 (189906)-binding sites, but no
TATA-like sequences.
MAPPING
By genomic sequence analysis, Kang et al. (2004) mapped the PNPO gene to
chromosome 17q21.32. They mapped the mouse gene to chromosome 11.
MOLECULAR GENETICS
In 5 patients from 3 families with PNPO deficiency (610090), Mills et
al. (2005) identified homozygous missense, splice site, and stop codon
mutations in the PNPO gene. Expression studies in Chinese hamster ovary
cells showed that the splice site (IVS3-1G-A; 603287.0002) and stop
codon (X262Q; 603287.0003) mutations were null activity mutations and
that the missense mutation (R229W; 603287.0001) markedly reduced
pyridox(am)ine phosphate oxidase activity. The authors suggested that
maintenance of optimal PLP levels in the brain may be important in many
neurologic disorders in which neurotransmitter metabolism is disturbed
(either as a primary or as a secondary phenomenon).
*FIELD* AV
.0001
PYRIDOXAMINE 5-PRIME-PHOSPHATE OXIDASE DEFICIENCY
PNPO, ARG229TRP
In twin boys, the children of consanguineous Turkish parents, with PNPO
deficiency (610090), Mills et al. (2005) detected a homozygous C-to-T
transition in exon 7 of the PNPO gene, resulting in a substitution of
tryptophan for the conserved arginine-229 residue (R229W). At least 4
and possibly 6 sibs from this family, including the twins, died from the
same disorder. Brautigam et al. (2002) had described the clinical and
laboratory findings in these patients.
.0002
PYRIDOXAMINE 5-PRIME-PHOSPHATE OXIDASE DEFICIENCY
PNPO, IVS3, G-A, -1
In an infant with PNPO deficiency (610090), Mills et al. (2005) found a
splice mutation in intron 3 (IVS3-1G-A) on 1 allele of the PNPO gene.
The missense mutation carried by the other allele was considered to be a
polymorphism. The parents were second cousins of East African Asian
origin. Patient fibroblast mRNA lacked exon 4, confirming aberrant
splicing. This patient was the only one studied by Mills et al. (2005)
to receive PLP treatment and to survive beyond the neonatal period, but
showed persistent central hypotonia and painful dystonic spasms as well
as some seizures by the second year of life. He had marked acquired
microcephaly and moderate to severe developmental delay.
.0003
PYRIDOXAMINE 5-PRIME-PHOSPHATE OXIDASE DEFICIENCY
PNPO, TER262GLN
In 2 affected sibs from a consanguineous Pakistani family with PNPO
deficiency (610090), Mills et al. (2005) detected a homozygous T-to-C
transition in exon 7 of the PNPO gene that resulted in substitution of
glutamine for the stop codon at position 262 (X262Q) and the addition of
28 amino acids. Expression studies demonstrated that X262Q PNPO is a
null activity mutant.
.0004
PYRIDOXAMINE 5-PRIME-PHOSPHATE OXIDASE DEFICIENCY
PNPO, ALA174TER
In a male infant with PNPO deficiency (610090), Ruiz et al. (2008)
identified a homozygous 520C-T transition in exon 5 of the PNPO gene,
resulting in an ala174-to-ter (A174X) substitution. The patient had
severe seizures and myoclonus within the first hours of life and died at
age 48 days.
*FIELD* RF
1. Brautigam, C.; Hyland, K.; Wevers, R.; Sharma, R.; Wagner, L.;
Stock, G.-J.; Heitmann, F.; Hoffmann, G. F.: Clinical and laboratory
findings in twins with neonatal epileptic encephalopathy mimicking
aromatic L-amino acid decarboxylase deficiency. Neuropediatrics 33:
113-117, 2002.
2. Kang, J. H.; Hong, M.-L.; Kim, D. W.; Park, J.; Kang, T.-C.; Won,
M. H.; Baek, N.-I.; Moon, B. J.; Choi, S. Y.; Kwon, O.-S.: Genomic
organization, tissue distribution and deletion mutation of human pyridoxine
5-prime-phosphate oxidase. Europ. J. Biochem. 271: 2452-2461, 2004.
3. Mills, P. B.; Surtees, R. A. H.; Champion, M. P.; Beesley, C. E.;
Dalton, N.; Scambler, P. J.; Heales, S. J. R.; Briddon, A.; Schmeimberg,
I.; Hoffmann, G. F.; Zschocke, J.; Clayton, P. T.: Neonatal epileptic
encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine
5-prime-phosphate oxidase. Hum. Molec. Genet. 14: 1077-1086, 2005.
4. Ngo, E. O.; LePage, G. R.; Thanassi, J. W.; Meisler, N.; Nutter,
L. M.: Absence of pyridoxine-5-prime-phosphate oxidase (PNPO) activity
in neoplastic cells: isolation, characterization, and expression of
PNPO cDNA. Biochemistry 37: 7741-7748, 1998.
5. Ruiz, A.; Garcia-Villoria, J.; Ormazabal, A.; Zschocke, J.; Fiol,
M.; Navarro-Sastre, A.; Artuch, R.; Vilaseca, M. A.; Ribes, A.: A
new fatal case of pyridox(am)ine 5-prime-phosphate oxidase (PNPO)
deficiency. Molec. Genet. Metab. 93: 216-218, 2008.
*FIELD* CN
Cassandra L. Kniffin - updated: 3/3/2008
George E. Tiller - updated: 5/8/2006
Patricia A. Hartz - updated: 8/16/2004
*FIELD* CD
Jennifer P. Macke: 11/13/1998
*FIELD* ED
wwang: 03/03/2008
ckniffin: 3/3/2008
alopez: 5/16/2006
alopez: 5/9/2006
alopez: 5/8/2006
alopez: 1/20/2006
mgross: 9/8/2004
terry: 8/16/2004
carol: 8/5/2004
alopez: 1/11/1999
alopez: 11/13/1998
MIM
610090
*RECORD*
*FIELD* NO
610090
*FIELD* TI
#610090 PYRIDOXAMINE 5-PRIME-PHOSPHATE OXIDASE DEFICIENCY
;;PNPO DEFICIENCY;;
SEIZURES, PYRIDOXINE-RESISTANT, PLP-SENSITIVE;;
read moreEPILEPTIC ENCEPHALOPATHY, NEONATAL, PNPO-RELATED
*FIELD* TX
A number sign (#) is used with this entry because pyridoxamine
5-prime-phosphate oxidase deficiency can be caused by mutation in the
PNPO gene (603287).
CLINICAL FEATURES
Brautigam et al. (2002) described twins, born of first-cousin parents,
who were born at 29 weeks' gestation and suffered from birth from severe
convulsions, myoclonus, rotatory eye movements, sudden clonic
contractions, burst suppression electroencephalogram (EEG),
hypoglycemia, and acidosis. In cerebrospinal fluid and urine a
biochemical pattern indicative of aromatic L-amino acid decarboxylase
(AADC) deficiency (608643) was found. Unexpectedly, AADC activity in
plasma was highly elevated rather than decreased, while enzyme activity
was absent in liver. Molecular analysis excluded genetic defect in the
AADC gene (107930).
Clayton et al. (2003) presented a boy born at 35 weeks' gestation by
cesarean section for fetal distress. His consanguineous parents were of
East African Asian origin. Seizures commenced on day 1 and rapidly
progressed to status epilepticus. Electroencephalogram showed severe
generalized burst suppression. Biochemistry was suggestive of reduced
AADC activity. Seizures responded dramatically to pyridoxal phosphate
(PLP).
In a study of 5 patients, including those of Brautigam et al. (2002) and
Clayton et al. (2003), with PNPO deficiency, Mills et al. (2005)
reviewed the phenotype. All patients were born prematurely and all but
one had low Apgar scores and/or required intubation. Early acidosis was
also common. Thus, PNPO deficiency must enter the differential diagnosis
of hypoxic-ischemic encephalopathy in a prematurely born infant.
Seizures commenced on the first day of life, with EEG showing a burst
suppression pattern. Biochemical abnormalities in CSF and urine were as
for AADC deficiency with the additional features of raised glycine (in
all 5), threonine (4 of 5), taurine (4 of 5), histidine (all 5), and low
arginine (3 of 5).
Ruiz et al. (2008) reported a male infant with PNPO deficiency. The
mother reported repetitive fetal rhythmic movements 2 weeks before
delivery, thought to be related to seizures. At birth he had a faltering
cry, hypersalivation with orobuccal rhythmic movements accompanied by
myoclonus and marked hyperexcitability requiring intubation and
ventilation. EEG showed severe myoclonic epilepsy. Brain imaging at 23,
25, and 35 days showed progressive hypomyelination and global atrophy.
Laboratory studies showed anemia, leukopenia, thrombocytopenia, and
coagulopathy. Analysis of urinary organic acids, plasma amino acids, and
CSF neurotransmitters suggested PNPO deficiency. He died of multiorgan
failure due to uncontrollable fungal infection at 48 days of life.
Genetic analysis identified a homozygous mutation in the PNPO gene
(603287.0004). Prenatal diagnosis using chorionic villus sampling in a
subsequent pregnancy identified the same homozygous mutation in the
fetus.
MOLECULAR GENETICS
Among 5 patients in 3 families with neonatal epileptic encephalopathy,
Mills et al. (2005) found evidence in cerebrospinal fluid and urine for
reduced activity of aromatic L-amino acid decarboxylase (AADC; 107930)
and other PLP-dependent enzymes. Seizures ceased with the administration
of PLP, having been resistant to treatment with pyridoxine, suggesting a
defect of pyridox(am)ine 5-prime-phosphate oxidase (PNPO; 603287).
Sequencing of the PNPO gene identified homozygous missense, splice site,
and stop codon mutations. Expression studies in Chinese hamster ovary
cells showed that the splice site (IVS3-1G-A; 603287.0002) and stop
codon (X262Q; 603287.0003) mutations were null activity mutations and
that the missense mutation (R229W; 603287.0001) markedly reduced
pyridox(am)ine phosphate oxidase activity. The authors suggested that
maintenance of optimal PLP levels in the brain may be important in many
neurologic disorders in which neurotransmitter metabolism is disturbed
(either as a primary or as a secondary phenomenon). Only one infant,
treated with PLP, survived the newborn period, but exhibited seizures,
dystonic spasms, microcephaly, and severe developmental delay at 2 years
of age.
*FIELD* RF
1. Brautigam, C.; Hyland, K.; Wevers, R.; Sharma, R.; Wagner, L.;
Stock, G.-J.; Heitmann, F.; Hoffmann, G. F.: Clinical and laboratory
findings in twins with neonatal epileptic encephalopathy mimicking
aromatic L-amino acid decarboxylase deficiency. Neuropediatrics 33:
113-117, 2002.
2. Clayton, P. T.; Surtees, R. A. H.; DeVile, C.; Hyland, K.; Heales,
S. J. R.: Neonatal epileptic encephalopathy. Lancet 361: 1614 only,
2003.
3. Mills, P. B.; Surtees, R. A. H.; Champion, M. P.; Beesley, C. E.;
Dalton, N.; Scambler, P. J.; Heales, S. J. R.; Briddon, A.; Scheimberg,
I.; Hoffmann, G. F.; Zschocke, J.; Clayton, P. T.: Neonatal epileptic
encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine
5-prime-phosphate oxidase. Hum. Molec. Genet. 14: 1077-1086, 2005.
4. Ruiz, A.; Garcia-Villoria, J.; Ormazabal, A.; Zschocke, J.; Fiol,
M.; Navarro-Sastre, A.; Artuch, R.; Vilaseca, M. A.; Ribes, A.: A
new fatal case of pyridox(am)ine 5-prime-phosphate oxidase (PNPO)
deficiency. Molec. Genet. Metab. 93: 216-218, 2008.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive
HEAD AND NECK:
[Head];
Microcephaly, progressive
ABDOMEN:
[Gastrointestinal];
Feeding problems
NEUROLOGIC:
[Central nervous system];
Neonatal epileptic encephalopathy (NEE);
Burst suppression on EEG;
Seizures;
Myoclonus;
Partial response to pyridoxine;
Response to pyridoxal phosphate;
Hypotonia, truncal
METABOLIC FEATURES:
Metabolic acidosis
HEMATOLOGY:
Anemia
PRENATAL MANIFESTATIONS:
[Delivery];
Preterm delivery;
Low APGAR scores
LABORATORY ABNORMALITIES:
Increased blood lactate;
Hypoglycemia;
Normal to increased plasma glycine;
Normal to increased plasma threonine;
Decreased plasma arginine;
Increased urine vanillactic acid (VLA);
Decreased CSF homovanillic acid (HVA);
Decreased CSF 5-hydroxyindoleacetic acid (5HIAA);
Increased CSF 3-methoxytyrosine (3-MT);
Increased CSF glycine;
Increased CSF threonine;
Increased CSF taurine;
Increased CSF histidine;
Decreased CSF arginine;
Decreased CSF pyridoxal;
Decreased CSF pyridoxal 5-prime-phosphate (PLP)
MISCELLANEOUS:
Onset 0-12 hours after birth
MOLECULAR BASIS:
Caused by mutation in the pyridoxamine 5-prime-phosphate oxidase gene
(PNPO, 603287.0001)
*FIELD* CD
Kelly A. Przylepa: 6/27/2007
*FIELD* ED
joanna: 03/10/2008
joanna: 6/27/2007
alopez: 5/9/2006
*FIELD* CN
Cassandra L. Kniffin - updated: 3/3/2008
Anne M. Stumpf - updated: 5/9/2006
*FIELD* CD
George E. Tiller: 5/8/2006
*FIELD* ED
wwang: 03/03/2008
ckniffin: 3/3/2008
alopez: 5/9/2006
*RECORD*
*FIELD* NO
610090
*FIELD* TI
#610090 PYRIDOXAMINE 5-PRIME-PHOSPHATE OXIDASE DEFICIENCY
;;PNPO DEFICIENCY;;
SEIZURES, PYRIDOXINE-RESISTANT, PLP-SENSITIVE;;
read moreEPILEPTIC ENCEPHALOPATHY, NEONATAL, PNPO-RELATED
*FIELD* TX
A number sign (#) is used with this entry because pyridoxamine
5-prime-phosphate oxidase deficiency can be caused by mutation in the
PNPO gene (603287).
CLINICAL FEATURES
Brautigam et al. (2002) described twins, born of first-cousin parents,
who were born at 29 weeks' gestation and suffered from birth from severe
convulsions, myoclonus, rotatory eye movements, sudden clonic
contractions, burst suppression electroencephalogram (EEG),
hypoglycemia, and acidosis. In cerebrospinal fluid and urine a
biochemical pattern indicative of aromatic L-amino acid decarboxylase
(AADC) deficiency (608643) was found. Unexpectedly, AADC activity in
plasma was highly elevated rather than decreased, while enzyme activity
was absent in liver. Molecular analysis excluded genetic defect in the
AADC gene (107930).
Clayton et al. (2003) presented a boy born at 35 weeks' gestation by
cesarean section for fetal distress. His consanguineous parents were of
East African Asian origin. Seizures commenced on day 1 and rapidly
progressed to status epilepticus. Electroencephalogram showed severe
generalized burst suppression. Biochemistry was suggestive of reduced
AADC activity. Seizures responded dramatically to pyridoxal phosphate
(PLP).
In a study of 5 patients, including those of Brautigam et al. (2002) and
Clayton et al. (2003), with PNPO deficiency, Mills et al. (2005)
reviewed the phenotype. All patients were born prematurely and all but
one had low Apgar scores and/or required intubation. Early acidosis was
also common. Thus, PNPO deficiency must enter the differential diagnosis
of hypoxic-ischemic encephalopathy in a prematurely born infant.
Seizures commenced on the first day of life, with EEG showing a burst
suppression pattern. Biochemical abnormalities in CSF and urine were as
for AADC deficiency with the additional features of raised glycine (in
all 5), threonine (4 of 5), taurine (4 of 5), histidine (all 5), and low
arginine (3 of 5).
Ruiz et al. (2008) reported a male infant with PNPO deficiency. The
mother reported repetitive fetal rhythmic movements 2 weeks before
delivery, thought to be related to seizures. At birth he had a faltering
cry, hypersalivation with orobuccal rhythmic movements accompanied by
myoclonus and marked hyperexcitability requiring intubation and
ventilation. EEG showed severe myoclonic epilepsy. Brain imaging at 23,
25, and 35 days showed progressive hypomyelination and global atrophy.
Laboratory studies showed anemia, leukopenia, thrombocytopenia, and
coagulopathy. Analysis of urinary organic acids, plasma amino acids, and
CSF neurotransmitters suggested PNPO deficiency. He died of multiorgan
failure due to uncontrollable fungal infection at 48 days of life.
Genetic analysis identified a homozygous mutation in the PNPO gene
(603287.0004). Prenatal diagnosis using chorionic villus sampling in a
subsequent pregnancy identified the same homozygous mutation in the
fetus.
MOLECULAR GENETICS
Among 5 patients in 3 families with neonatal epileptic encephalopathy,
Mills et al. (2005) found evidence in cerebrospinal fluid and urine for
reduced activity of aromatic L-amino acid decarboxylase (AADC; 107930)
and other PLP-dependent enzymes. Seizures ceased with the administration
of PLP, having been resistant to treatment with pyridoxine, suggesting a
defect of pyridox(am)ine 5-prime-phosphate oxidase (PNPO; 603287).
Sequencing of the PNPO gene identified homozygous missense, splice site,
and stop codon mutations. Expression studies in Chinese hamster ovary
cells showed that the splice site (IVS3-1G-A; 603287.0002) and stop
codon (X262Q; 603287.0003) mutations were null activity mutations and
that the missense mutation (R229W; 603287.0001) markedly reduced
pyridox(am)ine phosphate oxidase activity. The authors suggested that
maintenance of optimal PLP levels in the brain may be important in many
neurologic disorders in which neurotransmitter metabolism is disturbed
(either as a primary or as a secondary phenomenon). Only one infant,
treated with PLP, survived the newborn period, but exhibited seizures,
dystonic spasms, microcephaly, and severe developmental delay at 2 years
of age.
*FIELD* RF
1. Brautigam, C.; Hyland, K.; Wevers, R.; Sharma, R.; Wagner, L.;
Stock, G.-J.; Heitmann, F.; Hoffmann, G. F.: Clinical and laboratory
findings in twins with neonatal epileptic encephalopathy mimicking
aromatic L-amino acid decarboxylase deficiency. Neuropediatrics 33:
113-117, 2002.
2. Clayton, P. T.; Surtees, R. A. H.; DeVile, C.; Hyland, K.; Heales,
S. J. R.: Neonatal epileptic encephalopathy. Lancet 361: 1614 only,
2003.
3. Mills, P. B.; Surtees, R. A. H.; Champion, M. P.; Beesley, C. E.;
Dalton, N.; Scambler, P. J.; Heales, S. J. R.; Briddon, A.; Scheimberg,
I.; Hoffmann, G. F.; Zschocke, J.; Clayton, P. T.: Neonatal epileptic
encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine
5-prime-phosphate oxidase. Hum. Molec. Genet. 14: 1077-1086, 2005.
4. Ruiz, A.; Garcia-Villoria, J.; Ormazabal, A.; Zschocke, J.; Fiol,
M.; Navarro-Sastre, A.; Artuch, R.; Vilaseca, M. A.; Ribes, A.: A
new fatal case of pyridox(am)ine 5-prime-phosphate oxidase (PNPO)
deficiency. Molec. Genet. Metab. 93: 216-218, 2008.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive
HEAD AND NECK:
[Head];
Microcephaly, progressive
ABDOMEN:
[Gastrointestinal];
Feeding problems
NEUROLOGIC:
[Central nervous system];
Neonatal epileptic encephalopathy (NEE);
Burst suppression on EEG;
Seizures;
Myoclonus;
Partial response to pyridoxine;
Response to pyridoxal phosphate;
Hypotonia, truncal
METABOLIC FEATURES:
Metabolic acidosis
HEMATOLOGY:
Anemia
PRENATAL MANIFESTATIONS:
[Delivery];
Preterm delivery;
Low APGAR scores
LABORATORY ABNORMALITIES:
Increased blood lactate;
Hypoglycemia;
Normal to increased plasma glycine;
Normal to increased plasma threonine;
Decreased plasma arginine;
Increased urine vanillactic acid (VLA);
Decreased CSF homovanillic acid (HVA);
Decreased CSF 5-hydroxyindoleacetic acid (5HIAA);
Increased CSF 3-methoxytyrosine (3-MT);
Increased CSF glycine;
Increased CSF threonine;
Increased CSF taurine;
Increased CSF histidine;
Decreased CSF arginine;
Decreased CSF pyridoxal;
Decreased CSF pyridoxal 5-prime-phosphate (PLP)
MISCELLANEOUS:
Onset 0-12 hours after birth
MOLECULAR BASIS:
Caused by mutation in the pyridoxamine 5-prime-phosphate oxidase gene
(PNPO, 603287.0001)
*FIELD* CD
Kelly A. Przylepa: 6/27/2007
*FIELD* ED
joanna: 03/10/2008
joanna: 6/27/2007
alopez: 5/9/2006
*FIELD* CN
Cassandra L. Kniffin - updated: 3/3/2008
Anne M. Stumpf - updated: 5/9/2006
*FIELD* CD
George E. Tiller: 5/8/2006
*FIELD* ED
wwang: 03/03/2008
ckniffin: 3/3/2008
alopez: 5/9/2006