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 27-MAR-2024, entry version 231. 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}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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; 198. DR IntAct; P54886; 64. 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; 9606-ENSP00000360268; -. DR PeptideAtlas; P54886; -. DR ProteomicsDB; 56745; -. [P54886-1] DR ProteomicsDB; 56746; -. [P54886-2] DR Pumba; P54886; -. DR Antibodypedia; 2043; 241 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 AGR; HGNC:9722; -. 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; MGHAEGI; -. DR OrthoDB; 314297at2759; -. DR PhylomeDB; P54886; -. DR TreeFam; TF314372; -. DR BioCyc; MetaCyc:HS00730-MONOMER; -. 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; 80 hits in 1162 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 188 other cell types or tissues. DR GO; GO:0005743; C:mitochondrial inner membrane; TAS:Reactome. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. 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 GO; GO:0009266; P:response to temperature stimulus; IEA:Ensembl. DR CDD; cd04256; AAK_P5CS_ProBA; 1. DR CDD; cd07079; ALDH_F18-19_ProA-GPR; 1. DR Gene3D; 3.40.1160.10; Acetylglutamate kinase-like; 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 NCBIfam; TIGR01092; P5CS; 1. DR NCBIfam; TIGR00407; proA; 1. DR PANTHER; PTHR11063:SF8; DELTA-1-PYRROLINE-5-CARBOXYLATE SYNTHASE; 1. DR PANTHER; PTHR11063; GLUTAMATE SEMIALDEHYDE DEHYDROGENASE; 1. DR Pfam; PF00696; AA_kinase; 1. DR Pfam; PF00171; Aldedh; 1. DR PIRSF; PIRSF036429; P5C_syn; 1. DR PRINTS; PR00474; GLU5KINASE. DR SUPFAM; SSF53720; ALDH-like; 1. DR SUPFAM; SSF53633; Carbamate kinase-like; 1. DR PROSITE; PS00902; GLUTAMATE_5_KINASE; 1. DR PROSITE; PS01223; PROA; 1. DR Genevisible; P54886; HS. 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 FT glutamate-5-semialdehyde dehydrogenase activity; decreased FT amino acid 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; 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 //