P5CS_HUMAN
ID P5CS_HUMAN Reviewed; 795 AA.
AC P54886; B2R5Q4; B7Z350; B7Z5X8; B7ZLP1; D3DR44; O95952; Q3KQU2; Q5T566;
AC Q5T567; Q9UM72;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 30-MAY-2000, sequence version 2.
DT 03-AUG-2022, entry version 222.
DE RecName: Full=Delta-1-pyrroline-5-carboxylate synthase;
DE Short=P5CS;
DE AltName: Full=Aldehyde dehydrogenase family 18 member A1;
DE Includes:
DE RecName: Full=Glutamate 5-kinase;
DE Short=GK;
DE EC=2.7.2.11 {ECO:0000269|PubMed:26297558};
DE AltName: Full=Gamma-glutamyl kinase;
DE Includes:
DE RecName: Full=Gamma-glutamyl phosphate reductase;
DE Short=GPR;
DE EC=1.2.1.41 {ECO:0000269|PubMed:26297558};
DE AltName: Full=Glutamate-5-semialdehyde dehydrogenase;
DE AltName: Full=Glutamyl-gamma-semialdehyde dehydrogenase;
GN Name=ALDH18A1; Synonyms=GSAS, P5CS, PYCS;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG).
RC TISSUE=Kidney;
RX PubMed=8761662;
RA Aral B., Schlenzig J.S., Liu G., Kamoun P.;
RT "Database cloning human delta 1-pyrroline-5-carboxylate synthetase (P5CS)
RT cDNA: a bifunctional enzyme catalyzing the first 2 steps in proline
RT biosynthesis.";
RL C. R. Acad. Sci. III, Sci. Vie 319:171-178(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS LONG AND SHORT), FUNCTION, TISSUE
RP SPECIFICITY, AND ACTIVITY REGULATION (ISOFORMS LONG AND SHORT).
RC TISSUE=Small intestine;
RX PubMed=10037775; DOI=10.1074/jbc.274.10.6754;
RA Hu C.A., Lin W.-W., Obie C., Valle D.;
RT "Molecular enzymology of mammalian delta1-pyrroline-5-carboxylate synthase.
RT Alternative splice donor utilization generates isoforms with different
RT sensitivity to ornithine inhibition.";
RL J. Biol. Chem. 274:6754-6762(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LONG), AND VARIANT ILE-299.
RC TISSUE=Brain, and Hippocampus;
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., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., 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., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA 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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS LONG AND SHORT), AND
RP VARIANTS ILE-299 AND TYR-372.
RC TISSUE=Brain, and Uterus;
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY.
RC TISSUE=Lymphoblast;
RX PubMed=14654843; DOI=10.1038/nature02166;
RA Andersen J.S., Wilkinson C.J., Mayor T., Mortensen P., Nigg E.A., Mann M.;
RT "Proteomic characterization of the human centrosome by protein correlation
RT profiling.";
RL Nature 426:570-574(2003).
RN [8]
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., Buerckstuemmer T.,
RA 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 [9]
RP INVOLVEMENT IN ARCL3A, AND VARIANTS ARCL3A ARG-93 AND ILE-299.
RX PubMed=22170564; DOI=10.1007/s10545-011-9411-8;
RA Martinelli D., Haeberle J., Rubio V., Giunta C., Hausser I., Carrozzo R.,
RA Gougeard N., Marco-Marin C., Goffredo B.M., Meschini M.C., Bevivino E.,
RA Boenzi S., Colafati G.S., Brancati F., Baumgartner M.R., Dionisi-Vici C.;
RT "Understanding pyrroline-5-carboxylate synthetase deficiency: clinical,
RT molecular, functional, and expression studies, structure-based analysis,
RT and novel therapy with arginine.";
RL J. Inherit. Metab. Dis. 35:761-776(2012).
RN [10]
RP INVOLVEMENT IN ARCL3A, AND VARIANT ARCL3A CYS-782.
RX PubMed=24767728; DOI=10.1016/j.ejpn.2014.01.003;
RA Wolthuis D.F., van Asbeck E., Mohamed M., Gardeitchik T., Lim-Melia E.R.,
RA Wevers R.A., Morava E.;
RT "Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review
RT of the literature.";
RL Eur. J. Paediatr. Neurol. 18:511-515(2014).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [12]
RP FUNCTION, SUBCELLULAR LOCATION, SUBUNIT, INVOLVEMENT IN ADCL3, VARIANTS
RP ADCL3 GLN-138; LEU-138 AND TRP-138, AND CHARACTERIZATION OF VARIANT ADCL3
RP TRP-138.
RX PubMed=26320891; DOI=10.1016/j.ajhg.2015.08.001;
RA Fischer-Zirnsak B., Escande-Beillard N., Ganesh J., Tan Y.X.,
RA Al Bughaili M., Lin A.E., Sahai I., Bahena P., Reichert S.L., Loh A.,
RA Wright G.D., Liu J., Rahikkala E., Pivnick E.K., Choudhri A.F., Krueger U.,
RA Zemojtel T., van Ravenswaaij-Arts C., Mostafavi R., Stolte-Dijkstra I.,
RA Symoens S., Pajunen L., Al-Gazali L., Meierhofer D., Robinson P.N.,
RA Mundlos S., Villarroel C.E., Byers P., Masri A., Robertson S.P.,
RA Schwarze U., Callewaert B., Reversade B., Kornak U.;
RT "Recurrent de novo mutations affecting residue Arg138 of pyrroline-5-
RT carboxylate synthase cause a progeroid form of autosomal-dominant cutis
RT laxa.";
RL Am. J. Hum. Genet. 97:483-492(2015).
RN [13]
RP INVOLVEMENT IN SPG9A, INVOLVEMENT IN SPG9B, VARIANTS SPG9A ALA-120;
RP GLN-252; PHE-652 AND LEU-665, AND VARIANTS SPG9B HIS-128; PRO-637 AND
RP HIS-715.
RX PubMed=26026163; DOI=10.1093/brain/awv143;
RA Coutelier M., Goizet C., Durr A., Habarou F., Morais S., Dionne-Laporte A.,
RA Tao F., Konop J., Stoll M., Charles P., Jacoupy M., Matusiak R., Alonso I.,
RA Tallaksen C., Mairey M., Kennerson M., Gaussen M., Schule R., Janin M.,
RA Morice-Picard F., Durand C.M., Depienne C., Calvas P., Coutinho P.,
RA Saudubray J.M., Rouleau G., Brice A., Nicholson G., Darios F.,
RA Loureiro J.L., Zuchner S., Ottolenghi C., Mochel F., Stevanin G.;
RT "Alteration of ornithine metabolism leads to dominant and recessive
RT hereditary spastic paraplegia.";
RL Brain 138:2191-2205(2015).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [15]
RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, SUBUNIT, SUBCELLULAR LOCATION,
RP INVOLVEMENT IN SPG9A, VARIANTS SPG9A LEU-243 AND GLN-252, AND
RP CHARACTERIZATION OF VARIANTS SPG9A LEU-243 AND GLN-252.
RX PubMed=26297558; DOI=10.1093/brain/awv247;
RA Panza E., Escamilla-Honrubia J.M., Marco-Marin C., Gougeard N.,
RA De Michele G., Morra V.B., Liguori R., Salviati L., Donati M.A., Cusano R.,
RA Pippucci T., Ravazzolo R., Nemeth A.H., Smithson S., Davies S., Hurst J.A.,
RA Bordo D., Rubio V., Seri M.;
RT "ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of
RT function effect and plausibility of a dominant negative mechanism.";
RL Brain 139:E3-E3(2016).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 362-795.
RG Structural genomics consortium (SGC);
RT "Crystal structure of human pyrroline-5-carboxylate synthetase.";
RL Submitted (JUL-2011) to the PDB data bank.
RN [17]
RP VARIANT ARCL3A GLN-84, CHARACTERIZATION OF VARIANT ARCL3A GLN-84, FUNCTION,
RP AND CATALYTIC ACTIVITY.
RX PubMed=11092761; DOI=10.1093/hmg/9.19.2853;
RA Baumgartner M.R., Hu C.A., Almashanu S., Steel G., Obie C., Aral B.,
RA Rabier D., Kamoun P., Saudubray J.-M., Valle D.;
RT "Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a
RT new inborn error caused by a mutation in the gene encoding delta(1)-
RT pyrroline-5-carboxylate synthase.";
RL Hum. Mol. Genet. 9:2853-2858(2000).
RN [18]
RP VARIANT ARCL3A TYR-784, AND CHARACTERIZATION OF VARIANT ARCL3A TYR-784.
RX PubMed=18478038; DOI=10.1038/ejhg.2008.91;
RA Bicknell L.S., Pitt J., Aftimos S., Ramadas R., Maw M.A., Robertson S.P.;
RT "A missense mutation in ALDH18A1, encoding Delta1-pyrroline-5-carboxylate
RT synthase (P5CS), causes an autosomal recessive neurocutaneous syndrome.";
RL Eur. J. Hum. Genet. 16:1176-1186(2008).
CC -!- FUNCTION: Bifunctional enzyme that converts glutamate to glutamate 5-
CC semialdehyde, an intermediate in the biosynthesis of proline, ornithine
CC and arginine. {ECO:0000269|PubMed:10037775,
CC ECO:0000269|PubMed:11092761, ECO:0000269|PubMed:26297558,
CC ECO:0000269|PubMed:26320891}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-glutamate = ADP + L-glutamyl 5-phosphate;
CC Xref=Rhea:RHEA:14877, ChEBI:CHEBI:29985, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:58274, ChEBI:CHEBI:456216; EC=2.7.2.11;
CC Evidence={ECO:0000269|PubMed:26297558};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-glutamate 5-semialdehyde + NADP(+) + phosphate = H(+) + L-
CC glutamyl 5-phosphate + NADPH; Xref=Rhea:RHEA:19541,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:43474, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58066, ChEBI:CHEBI:58274, ChEBI:CHEBI:58349; EC=1.2.1.41;
CC Evidence={ECO:0000269|PubMed:26297558};
CC -!- ACTIVITY REGULATION: Isoform Short: Inhibited by L-ornithine with a Ki
CC of approximately 0.25 mm. Isoform Long: Insensitive to ornithine
CC inhibition. This is due to the two amino acid insert which abolishes
CC feedback inhibition of P5CS activity by L-ornithine.
CC {ECO:0000269|PubMed:10037775}.
CC -!- PATHWAY: Amino-acid biosynthesis; L-proline biosynthesis; L-glutamate
CC 5-semialdehyde from L-glutamate: step 1/2.
CC {ECO:0000269|PubMed:26297558}.
CC -!- PATHWAY: Amino-acid biosynthesis; L-proline biosynthesis; L-glutamate
CC 5-semialdehyde from L-glutamate: step 2/2.
CC {ECO:0000269|PubMed:26297558}.
CC -!- SUBUNIT: Homohexamer or homotetramer. {ECO:0000269|PubMed:26297558,
CC ECO:0000269|PubMed:26320891}.
CC -!- INTERACTION:
CC P54886; Q6RW13: AGTRAP; NbExp=3; IntAct=EBI-1210304, EBI-741181;
CC P54886; Q96DZ9: CMTM5; NbExp=3; IntAct=EBI-1210304, EBI-2548702;
CC P54886; O75208: COQ9; NbExp=3; IntAct=EBI-1210304, EBI-724524;
CC P54886; Q6PI48: DARS2; NbExp=3; IntAct=EBI-1210304, EBI-3917045;
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane
CC {ECO:0000269|PubMed:26297558, ECO:0000269|PubMed:26320891}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Long;
CC IsoId=P54886-1; Sequence=Displayed;
CC Name=Short;
CC IsoId=P54886-2; Sequence=VSP_005215;
CC -!- DISEASE: Cutis laxa, autosomal recessive, 3A (ARCL3A) [MIM:219150]: A
CC syndrome characterized by facial dysmorphism with a progeroid
CC appearance, large and late-closing fontanel, cutis laxa, joint
CC hyperlaxity, athetoid movements and hyperreflexia, pre- and postnatal
CC growth retardation, intellectual deficit, developmental delay, and
CC ophthalmologic abnormalities. {ECO:0000269|PubMed:11092761,
CC ECO:0000269|PubMed:18478038, ECO:0000269|PubMed:22170564,
CC ECO:0000269|PubMed:24767728}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Cutis laxa, autosomal dominant, 3 (ADCL3) [MIM:616603]: A form
CC of cutis laxa, a connective tissue disorder characterized by loose,
CC hyperextensible skin with decreased resilience and elasticity leading
CC to a premature aged appearance. Face, hands, feet, joints, and torso
CC may be differentially affected. Additional variable clinical features
CC are gastrointestinal diverticula, hernia, and genital prolapse. Rare
CC manifestations are pulmonary artery stenosis, aortic aneurysm,
CC bronchiectasis, and emphysema. ADCL3 patients manifest thin skin with
CC visible veins and wrinkles, cataract or corneal clouding, moderate
CC intellectual disability, muscular hypotonia with brisk muscle reflexes,
CC clenched fingers, and pre- and postnatal growth retardation.
CC {ECO:0000269|PubMed:26320891}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Spastic paraplegia 9A, autosomal dominant (SPG9A)
CC [MIM:601162]: A form of spastic paraplegia, a neurodegenerative
CC disorder characterized by a slow, gradual, progressive weakness and
CC spasticity of the lower limbs. Rate of progression and the severity of
CC symptoms are quite variable. Initial symptoms may include difficulty
CC with balance, weakness and stiffness in the legs, muscle spasms, and
CC dragging the toes when walking. In some forms of the disorder, bladder
CC symptoms (such as incontinence) may appear, or the weakness and
CC stiffness may spread to other parts of the body. SPG9A patients have
CC gait difficulties, motor neuropathy, and dysarthria. Additional
CC variable features include cerebellar signs, cataract, pes cavus, and
CC urinary urgency. {ECO:0000269|PubMed:26026163,
CC ECO:0000269|PubMed:26297558}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Spastic paraplegia 9B, autosomal recessive (SPG9B)
CC [MIM:616586]: A form of spastic paraplegia, a neurodegenerative
CC disorder characterized by a slow, gradual, progressive weakness and
CC spasticity of the lower limbs. Rate of progression and the severity of
CC symptoms are quite variable. Initial symptoms may include difficulty
CC with balance, weakness and stiffness in the legs, muscle spasms, and
CC dragging the toes when walking. In some forms of the disorder, bladder
CC symptoms (such as incontinence) may appear, or the weakness and
CC stiffness may spread to other parts of the body. SPG9B is a complex
CC form characterized by delayed psychomotor development, intellectual
CC disability, and severe motor impairment. Dysmorphic facial features,
CC tremor, and urinary incontinence are variably observed in SPG9B
CC patients. {ECO:0000269|PubMed:26026163}. Note=The disease is caused by
CC variants affecting the gene represented in this entry.
CC -!- SIMILARITY: In the N-terminal section; belongs to the glutamate 5-
CC kinase family. {ECO:0000305}.
CC -!- SIMILARITY: In the C-terminal section; belongs to the gamma-glutamyl
CC phosphate reductase family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAH12086.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAH13064.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; X94453; CAA64224.1; -; mRNA.
DR EMBL; U76542; AAD17454.1; -; mRNA.
DR EMBL; U68758; AAD00169.1; -; mRNA.
DR EMBL; AK295487; BAH12086.1; ALT_INIT; mRNA.
DR EMBL; AK299557; BAH13064.1; ALT_INIT; mRNA.
DR EMBL; AK312271; BAG35201.1; -; mRNA.
DR EMBL; AL356632; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471066; EAW49995.1; -; Genomic_DNA.
DR EMBL; CH471066; EAW49994.1; -; Genomic_DNA.
DR EMBL; CH471066; EAW49996.1; -; Genomic_DNA.
DR EMBL; CH471066; EAW49997.1; -; Genomic_DNA.
DR EMBL; BC106054; AAI06055.1; -; mRNA.
DR EMBL; BC117240; AAI17241.1; -; mRNA.
DR EMBL; BC117242; AAI17243.1; -; mRNA.
DR EMBL; BC143930; AAI43931.1; -; mRNA.
DR CCDS; CCDS31257.1; -. [P54886-2]
DR CCDS; CCDS7443.1; -. [P54886-1]
DR RefSeq; NP_001017423.1; NM_001017423.1. [P54886-2]
DR RefSeq; NP_001310341.1; NM_001323412.1.
DR RefSeq; NP_001310342.1; NM_001323413.1. [P54886-1]
DR RefSeq; NP_001310343.1; NM_001323414.1. [P54886-1]
DR RefSeq; NP_001310344.1; NM_001323415.1. [P54886-2]
DR RefSeq; NP_001310345.1; NM_001323416.1.
DR RefSeq; NP_001310348.1; NM_001323419.1.
DR RefSeq; NP_002851.2; NM_002860.3. [P54886-1]
DR PDB; 2H5G; X-ray; 2.25 A; A/B=362-795.
DR PDBsum; 2H5G; -.
DR AlphaFoldDB; P54886; -.
DR SMR; P54886; -.
DR BioGRID; 111790; 152.
DR IntAct; P54886; 57.
DR MINT; P54886; -.
DR STRING; 9606.ENSP00000360268; -.
DR ChEMBL; CHEMBL4295784; -.
DR DrugBank; DB00142; Glutamic acid.
DR GlyGen; P54886; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P54886; -.
DR MetOSite; P54886; -.
DR PhosphoSitePlus; P54886; -.
DR SwissPalm; P54886; -.
DR BioMuta; ALDH18A1; -.
DR DMDM; 6226882; -.
DR CPTAC; CPTAC-11; -.
DR EPD; P54886; -.
DR jPOST; P54886; -.
DR MassIVE; P54886; -.
DR MaxQB; P54886; -.
DR PaxDb; P54886; -.
DR PeptideAtlas; P54886; -.
DR PRIDE; P54886; -.
DR ProteomicsDB; 56745; -. [P54886-1]
DR ProteomicsDB; 56746; -. [P54886-2]
DR Antibodypedia; 2043; 215 antibodies from 32 providers.
DR DNASU; 5832; -.
DR Ensembl; ENST00000371221.3; ENSP00000360265.3; ENSG00000059573.9. [P54886-2]
DR Ensembl; ENST00000371224.7; ENSP00000360268.2; ENSG00000059573.9. [P54886-1]
DR GeneID; 5832; -.
DR KEGG; hsa:5832; -.
DR MANE-Select; ENST00000371224.7; ENSP00000360268.2; NM_002860.4; NP_002851.2.
DR UCSC; uc001kky.4; human. [P54886-1]
DR CTD; 5832; -.
DR DisGeNET; 5832; -.
DR GeneCards; ALDH18A1; -.
DR HGNC; HGNC:9722; ALDH18A1.
DR HPA; ENSG00000059573; Tissue enhanced (salivary).
DR MalaCards; ALDH18A1; -.
DR MIM; 138250; gene.
DR MIM; 219150; phenotype.
DR MIM; 601162; phenotype.
DR MIM; 616586; phenotype.
DR MIM; 616603; phenotype.
DR neXtProt; NX_P54886; -.
DR OpenTargets; ENSG00000059573; -.
DR Orphanet; 35664; ALDH18A1-related De Barsy syndrome.
DR Orphanet; 90348; Autosomal dominant cutis laxa.
DR Orphanet; 447753; Autosomal dominant spastic paraplegia type 9A.
DR Orphanet; 447757; Autosomal dominant spastic paraplegia type 9B.
DR Orphanet; 447760; Autosomal recessive spastic paraplegia type 9B.
DR PharmGKB; PA34065; -.
DR VEuPathDB; HostDB:ENSG00000059573; -.
DR eggNOG; KOG1154; Eukaryota.
DR eggNOG; KOG4165; Eukaryota.
DR GeneTree; ENSGT00500000044903; -.
DR HOGENOM; CLU_016144_0_0_1; -.
DR InParanoid; P54886; -.
DR OMA; EGRECIM; -.
DR OrthoDB; 832430at2759; -.
DR PhylomeDB; P54886; -.
DR TreeFam; TF314372; -.
DR BioCyc; MetaCyc:HS00730-MON; -.
DR PathwayCommons; P54886; -.
DR Reactome; R-HSA-8964539; Glutamate and glutamine metabolism.
DR SignaLink; P54886; -.
DR UniPathway; UPA00098; UER00359.
DR UniPathway; UPA00098; UER00360.
DR BioGRID-ORCS; 5832; 76 hits in 1080 CRISPR screens.
DR ChiTaRS; ALDH18A1; human.
DR EvolutionaryTrace; P54886; -.
DR GeneWiki; Aldehyde_dehydrogenase_18_family,_member_A1; -.
DR GenomeRNAi; 5832; -.
DR Pharos; P54886; Tbio.
DR PRO; PR:P54886; -.
DR Proteomes; UP000005640; Chromosome 10.
DR RNAct; P54886; protein.
DR Bgee; ENSG00000059573; Expressed in parotid gland and 186 other tissues.
DR Genevisible; P54886; HS.
DR GO; GO:0005743; C:mitochondrial inner membrane; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004349; F:glutamate 5-kinase activity; IDA:UniProtKB.
DR GO; GO:0004350; F:glutamate-5-semialdehyde dehydrogenase activity; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IDA:UniProtKB.
DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB.
DR GO; GO:0019240; P:citrulline biosynthetic process; IMP:UniProtKB.
DR GO; GO:0006536; P:glutamate metabolic process; IMP:UniProtKB.
DR GO; GO:0055129; P:L-proline biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0006592; P:ornithine biosynthetic process; IMP:UniProtKB.
DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR GO; GO:0006561; P:proline biosynthetic process; IMP:UniProtKB.
DR CDD; cd04256; AAK_P5CS_ProBA; 1.
DR CDD; cd07079; ALDH_F18-19_ProA-GPR; 1.
DR Gene3D; 3.40.1160.10; -; 1.
DR Gene3D; 3.40.309.10; -; 1.
DR Gene3D; 3.40.605.10; -; 1.
DR HAMAP; MF_00412; ProA; 1.
DR HAMAP; MF_00456; ProB; 1.
DR InterPro; IPR036393; AceGlu_kinase-like_sf.
DR InterPro; IPR016161; Ald_DH/histidinol_DH.
DR InterPro; IPR016163; Ald_DH_C.
DR InterPro; IPR016162; Ald_DH_N.
DR InterPro; IPR015590; Aldehyde_DH_dom.
DR InterPro; IPR001048; Asp/Glu/Uridylate_kinase.
DR InterPro; IPR020593; G-glutamylP_reductase_CS.
DR InterPro; IPR041744; G5K_ProBA.
DR InterPro; IPR001057; Glu/AcGlu_kinase.
DR InterPro; IPR005715; Glu_5kinase/COase_Synthase.
DR InterPro; IPR019797; Glutamate_5-kinase_CS.
DR InterPro; IPR000965; GPR_dom.
DR InterPro; IPR005766; P5_carboxy_syn.
DR Pfam; PF00696; AA_kinase; 1.
DR Pfam; PF00171; Aldedh; 1.
DR PIRSF; PIRSF036429; P5C_syn; 1.
DR PRINTS; PR00474; GLU5KINASE.
DR SUPFAM; SSF53633; SSF53633; 1.
DR SUPFAM; SSF53720; SSF53720; 1.
DR TIGRFAMs; TIGR01092; P5CS; 1.
DR TIGRFAMs; TIGR00407; proA; 1.
DR PROSITE; PS00902; GLUTAMATE_5_KINASE; 1.
DR PROSITE; PS01223; PROA; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Amino-acid biosynthesis; ATP-binding;
KW Disease variant; Hereditary spastic paraplegia; Intellectual disability;
KW Kinase; Membrane; Mitochondrion; Mitochondrion inner membrane;
KW Multifunctional enzyme; NADP; Neurodegeneration; Nucleotide-binding;
KW Oxidoreductase; Proline biosynthesis; Reference proteome; Transferase.
FT CHAIN 1..795
FT /note="Delta-1-pyrroline-5-carboxylate synthase"
FT /id="PRO_0000109769"
FT REGION 1..361
FT /note="Glutamate 5-kinase"
FT REGION 362..795
FT /note="Gamma-glutamyl phosphate reductase"
FT BINDING 117
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 223
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 246
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 266..267
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 305..311
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT MOD_RES 311
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z110"
FT MOD_RES 347
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z110"
FT MOD_RES 550
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z110"
FT VAR_SEQ 239..240
FT /note="Missing (in isoform Short)"
FT /evidence="ECO:0000303|PubMed:10037775,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_005215"
FT VARIANT 84
FT /note="R -> Q (in ARCL3A; reduction of activity;
FT dbSNP:rs121434582)"
FT /evidence="ECO:0000269|PubMed:11092761"
FT /id="VAR_038482"
FT VARIANT 93
FT /note="G -> R (in ARCL3A)"
FT /evidence="ECO:0000269|PubMed:22170564"
FT /id="VAR_075884"
FT VARIANT 120
FT /note="V -> A (in SPG9A; dbSNP:rs863224945)"
FT /evidence="ECO:0000269|PubMed:26026163"
FT /id="VAR_075885"
FT VARIANT 128
FT /note="R -> H (in SPG9B; dbSNP:rs768323248)"
FT /evidence="ECO:0000269|PubMed:26026163"
FT /id="VAR_075886"
FT VARIANT 138
FT /note="R -> L (in ADCL3; dbSNP:rs863225045)"
FT /evidence="ECO:0000269|PubMed:26320891"
FT /id="VAR_075887"
FT VARIANT 138
FT /note="R -> Q (in ADCL3; dbSNP:rs863225045)"
FT /evidence="ECO:0000269|PubMed:26320891"
FT /id="VAR_075888"
FT VARIANT 138
FT /note="R -> W (in ADCL3; no effect on protein abundance;
FT altered sub-mitochondrial distribution; decreased proline
FT biosynthetic process; dbSNP:rs863225044)"
FT /evidence="ECO:0000269|PubMed:26320891"
FT /id="VAR_075889"
FT VARIANT 243
FT /note="V -> L (in SPG9A; decreased protein abundance; no
FT effect on localization to the mitochondrion; altered
FT homohexamerization; loss of glutamate 5-kinase activity; no
FT effect on glutamate-5-semialdehyde dehydrogenase activity;
FT decreased amino acid biosynthetic process;
FT dbSNP:rs864321669)"
FT /evidence="ECO:0000269|PubMed:26297558"
FT /id="VAR_075890"
FT VARIANT 252
FT /note="R -> Q (in SPG9A; altered homohexamerization; no
FT effect on localization to the mitochondrion; loss of
FT glutamate 5-kinase activity; no effect on glutamate-5-
FT semialdehyde dehydrogenase activity; decreased amino acid
FT biosynthetic process; dbSNP:rs864321670)"
FT /evidence="ECO:0000269|PubMed:26026163,
FT ECO:0000269|PubMed:26297558"
FT /id="VAR_075891"
FT VARIANT 299
FT /note="T -> I (in ARCL3A; benign variant; dbSNP:rs2275272)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:22170564"
FT /id="VAR_051792"
FT VARIANT 372
FT /note="S -> Y (in dbSNP:rs3765571)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_051793"
FT VARIANT 637
FT /note="L -> P (in SPG9B; dbSNP:rs869320690)"
FT /evidence="ECO:0000269|PubMed:26026163"
FT /id="VAR_075892"
FT VARIANT 652
FT /note="S -> F (in SPG9A)"
FT /evidence="ECO:0000269|PubMed:26026163"
FT /id="VAR_075893"
FT VARIANT 665
FT /note="R -> L (in SPG9A; dbSNP:rs766264810)"
FT /evidence="ECO:0000269|PubMed:26026163"
FT /id="VAR_075894"
FT VARIANT 715
FT /note="D -> H (in SPG9B; dbSNP:rs752669339)"
FT /evidence="ECO:0000269|PubMed:26026163"
FT /id="VAR_075895"
FT VARIANT 782
FT /note="Y -> C (in ARCL3A; dbSNP:rs774047299)"
FT /evidence="ECO:0000269|PubMed:24767728"
FT /id="VAR_075896"
FT VARIANT 784
FT /note="H -> Y (in ARCL3A; does not affect proline and
FT ornithine biosynthetic activity; dbSNP:rs121434583)"
FT /evidence="ECO:0000269|PubMed:18478038"
FT /id="VAR_058006"
FT CONFLICT 87
FT /note="E -> K (in Ref. 3; BAG35201)"
FT /evidence="ECO:0000305"
FT CONFLICT 126
FT /note="R -> T (in Ref. 1; CAA64224)"
FT /evidence="ECO:0000305"
FT CONFLICT 266
FT /note="S -> P (in Ref. 1; CAA64224)"
FT /evidence="ECO:0000305"
FT CONFLICT 299
FT /note="T -> P (in Ref. 1; CAA64224)"
FT /evidence="ECO:0000305"
FT CONFLICT 305..307
FT /note="MGG -> NGC (in Ref. 1; CAA64224)"
FT /evidence="ECO:0000305"
FT CONFLICT 314..315
FT /note="AA -> ST (in Ref. 1; CAA64224)"
FT /evidence="ECO:0000305"
FT CONFLICT 487..493
FT /note="LPQVAAL -> PTPGGSF (in Ref. 1; CAA64224)"
FT /evidence="ECO:0000305"
FT HELIX 363..379
FT /evidence="ECO:0007829|PDB:2H5G"
FT HELIX 382..398
FT /evidence="ECO:0007829|PDB:2H5G"
FT HELIX 400..414
FT /evidence="ECO:0007829|PDB:2H5G"
FT TURN 415..417
FT /evidence="ECO:0007829|PDB:2H5G"
FT HELIX 420..424
FT /evidence="ECO:0007829|PDB:2H5G"
FT HELIX 430..446
FT /evidence="ECO:0007829|PDB:2H5G"
FT STRAND 454..461
FT /evidence="ECO:0007829|PDB:2H5G"
FT STRAND 464..472
FT /evidence="ECO:0007829|PDB:2H5G"
FT STRAND 475..482
FT /evidence="ECO:0007829|PDB:2H5G"
FT HELIX 486..497
FT /evidence="ECO:0007829|PDB:2H5G"
FT STRAND 500..504
FT /evidence="ECO:0007829|PDB:2H5G"
FT HELIX 507..509
FT /evidence="ECO:0007829|PDB:2H5G"
FT HELIX 510..525
FT /evidence="ECO:0007829|PDB:2H5G"
FT TURN 526..528
FT /evidence="ECO:0007829|PDB:2H5G"
FT HELIX 530..532
FT /evidence="ECO:0007829|PDB:2H5G"
FT STRAND 533..535
FT /evidence="ECO:0007829|PDB:2H5G"
FT STRAND 553..559
FT /evidence="ECO:0007829|PDB:2H5G"
FT HELIX 561..570
FT /evidence="ECO:0007829|PDB:2H5G"
FT STRAND 572..574
FT /evidence="ECO:0007829|PDB:2H5G"
FT STRAND 584..588
FT /evidence="ECO:0007829|PDB:2H5G"
FT TURN 594..596
FT /evidence="ECO:0007829|PDB:2H5G"
FT HELIX 597..606
FT /evidence="ECO:0007829|PDB:2H5G"
FT STRAND 614..621
FT /evidence="ECO:0007829|PDB:2H5G"
FT HELIX 622..624
FT /evidence="ECO:0007829|PDB:2H5G"
FT HELIX 628..639
FT /evidence="ECO:0007829|PDB:2H5G"
FT STRAND 643..646
FT /evidence="ECO:0007829|PDB:2H5G"
FT HELIX 648..651
FT /evidence="ECO:0007829|PDB:2H5G"
FT STRAND 670..680
FT /evidence="ECO:0007829|PDB:2H5G"
FT HELIX 681..691
FT /evidence="ECO:0007829|PDB:2H5G"
FT STRAND 694..700
FT /evidence="ECO:0007829|PDB:2H5G"
FT HELIX 704..713
FT /evidence="ECO:0007829|PDB:2H5G"
FT STRAND 716..723
FT /evidence="ECO:0007829|PDB:2H5G"
FT HELIX 725..727
FT /evidence="ECO:0007829|PDB:2H5G"
FT TURN 730..734
FT /evidence="ECO:0007829|PDB:2H5G"
FT STRAND 745..747
FT /evidence="ECO:0007829|PDB:2H5G"
FT HELIX 754..757
FT /evidence="ECO:0007829|PDB:2H5G"
FT STRAND 758..765
FT /evidence="ECO:0007829|PDB:2H5G"
FT HELIX 771..774
FT /evidence="ECO:0007829|PDB:2H5G"
SQ SEQUENCE 795 AA; 87302 MW; 8BF27EF2A8FB2D79 CRC64;
MLSQVYRCGF QPFNQHLLPW VKCTTVFRSH CIQPSVIRHV RSWSNIPFIT VPLSRTHGKS
FAHRSELKHA KRIVVKLGSA VVTRGDECGL ALGRLASIVE QVSVLQNQGR EMMLVTSGAV
AFGKQRLRHE ILLSQSVRQA LHSGQNQLKE MAIPVLEARA CAAAGQSGLM ALYEAMFTQY
SICAAQILVT NLDFHDEQKR RNLNGTLHEL LRMNIVPIVN TNDAVVPPAE PNSDLQGVNV
ISVKDNDSLA ARLAVEMKTD LLIVLSDVEG LFDSPPGSDD AKLIDIFYPG DQQSVTFGTK
SRVGMGGMEA KVKAALWALQ GGTSVVIANG THPKVSGHVI TDIVEGKKVG TFFSEVKPAG
PTVEQQGEMA RSGGRMLATL EPEQRAEIIH HLADLLTDQR DEILLANKKD LEEAEGRLAA
PLLKRLSLST SKLNSLAIGL RQIAASSQDS VGRVLRRTRI AKNLELEQVT VPIGVLLVIF
ESRPDCLPQV AALAIASGNG LLLKGGKEAA HSNRILHLLT QEALSIHGVK EAVQLVNTRE
EVEDLCRLDK MIDLIIPRGS SQLVRDIQKA AKGIPVMGHS EGICHMYVDS EASVDKVTRL
VRDSKCEYPA ACNALETLLI HRDLLRTPLF DQIIDMLRVE QVKIHAGPKF ASYLTFSPSE
VKSLRTEYGD LELCIEVVDN VQDAIDHIHK YGSSHTDVIV TEDENTAEFF LQHVDSACVF
WNASTRFSDG YRFGLGAEVG ISTSRIHARG PVGLEGLLTT KWLLRGKDHV VSDFSEHGSL
KYLHENLPIP QRNTN
