Reviewed, UniProtKB/Swiss-Prot P54886 (P5CS_HUMAN)

Names and origin

Protein names

Recommended name:
    Delta-1-pyrroline-5-carboxylate synthetase
      Short name=P5CS
Alternative name(s):
    Aldehyde dehydrogenase family 18 member A1
Including the following 2 domains:
    1- Recommended name:
            Glutamate 5-kinase
                Short name=GK
              EC=2.7.2.11
        Alternative name(s):
            Gamma-glutamyl kinase
    2- Recommended name:
            Gamma-glutamyl phosphate reductase
                Short name=GPR
              EC=1.2.1.41
        Alternative name(s):
            Glutamate-5-semialdehyde dehydrogenase
            Glutamyl-gamma-semialdehyde dehydrogenase

Gene names

Name:	ALDH18A1
Synonyms:	GSAS, P5CS, PYCS

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	795 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Catalytic activity	ATP + L-glutamate = ADP + L-glutamate 5-phosphate. L-glutamate 5-semialdehyde + phosphate + NADP(+) = L-glutamyl 5-phosphate + NADPH.
Enzyme regulation	The short isoform is inhibited by L-ornithine with a Ki of approximately 0.25 mm. The long isoform is insensitive to ornithine inhibition. Thus, the two amino acid insert in the long isoform abolishes feedback inhibition of P5CS activity by L-ornithine.
Pathway	Amino-acid biosynthesis; L-proline biosynthesis; L-glutamate 5-semialdehyde from L-glutamate: step 1/2. Amino-acid biosynthesis; L-proline biosynthesis; L-glutamate 5-semialdehyde from L-glutamate: step 2/2.
Subcellular location	Mitochondrion inner membrane.
Involvement in disease	Defects in ALDH18A1 are the cause of delta-1-pyrroline-5-carboxylate synthetase deficiency (P5CS deficiency) [MIM:138250]. P5CS deficiency leads to progressive neurodegeneration, joint laxity, skin hyperelasticity and bilateral subcapsular cataracts. The metabolic phenotype includes hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia.
Sequence similarities	In the N-terminal section; belongs to the glutamate 5-kinase family. In the C-terminal section; belongs to the gamma-glutamyl phosphate reductase family.

Ontologies

Keywords
Biological process	Amino-acid biosynthesis Proline biosynthesis
Cellular component	Membrane Mitochondrion Mitochondrion inner membrane
Coding sequence diversity	Alternative splicing
Disease	Disease mutation
Ligand	NADP
Molecular function	Kinase Oxidoreductase Transferase
Technical term	3D-structure Multifunctional enzyme
Gene Ontology (GO)
Biological process	oxidation reduction Inferred from electronic annotation. Source: UniProtKB-KW proline biosynthetic process Ref.1 Traceable author statement. Source: ProtInc
Cellular component	mitochondrial inner membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	glutamate 5-kinase activity Inferred from electronic annotation. Source: InterPro glutamate-5-semialdehyde dehydrogenase activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform Long (identifier: P54886-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform Short (identifier: P54886-2)

The sequence of this isoform differs from the canonical sequence as follows:
     239-240: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 795

795

Delta-1-pyrroline-5-carboxylate synthetase

PRO_0000109769

Regions

Region

1 – 361

361

Glutamate 5-kinase

Region

362 – 795

434

Gamma-glutamyl phosphate reductase

Natural variations

Alternative sequence

239 – 240

2

Missing in isoform Short.

VSP_005215

Natural variant

84

1

R → Q in P5CS deficiency; reduction of activity.

VAR_038482

Experimental info

Sequence conflict

126

1

R → T in CAA64224. Ref.1

Sequence conflict

266

1

S → P in CAA64224. Ref.1

Sequence conflict

299

1

T → P in CAA64224. Ref.1

Sequence conflict

305 – 307

3

MGG → NGC in CAA64224. Ref.1

Sequence conflict

314 – 315

2

AA → ST in CAA64224. Ref.1

Sequence conflict

487 – 493

7

LPQVAAL → PTPGGSF in CAA64224. Ref.1

Secondary structure

1

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795

Helix Strand Turn

Details...

Helix

363 – 379

17

Helix

382 – 398

17

Helix

400 – 414

15

Turn

415 – 417

3

Helix

420 – 424

5

Helix

430 – 446

17

Beta strand

454 – 461

8

Beta strand

464 – 472

9

Beta strand

475 – 482

8

Helix

486 – 497

12

Beta strand

500 – 504

5

Helix

507 – 509

3

Helix

510 – 525

16

Turn

526 – 528

3

Helix

530 – 532

3

Beta strand

533 – 535

3

Beta strand

553 – 559

7

Helix

561 – 570

10

Beta strand

572 – 574

3

Beta strand

584 – 588

5

Turn

594 – 596

3

Helix

597 – 606

10

Beta strand

614 – 621

8

Helix

622 – 624

3

Helix

628 – 639

12

Beta strand

643 – 646

4

Helix

648 – 651

4

Beta strand

670 – 680

11

Helix

681 – 691

11

Beta strand

694 – 700

7

Helix

704 – 713

10

Beta strand

716 – 723

8

Helix

725 – 727

3

Turn

730 – 734

5

Beta strand

745 – 747

3

Helix

754 – 757

4

Beta strand

758 – 769

12

Helix

771 – 774

4

Sequences

	Sequence		Length	Mass (Da)
	Isoform Long [UniParc]. Last modified May 30, 2000. Version 2. Checksum: 8BF27EF2A8FB2D79	FASTA	795	87,302
	10 20 30 40 50 60 MLSQVYRCGF QPFNQHLLPW VKCTTVFRSH CIQPSVIRHV RSWSNIPFIT VPLSRTHGKS 70 80 90 100 110 120 FAHRSELKHA KRIVVKLGSA VVTRGDECGL ALGRLASIVE QVSVLQNQGR EMMLVTSGAV 130 140 150 160 170 180 AFGKQRLRHE ILLSQSVRQA LHSGQNQLKE MAIPVLEARA CAAAGQSGLM ALYEAMFTQY 190 200 210 220 230 240 SICAAQILVT NLDFHDEQKR RNLNGTLHEL LRMNIVPIVN TNDAVVPPAE PNSDLQGVNV 250 260 270 280 290 300 ISVKDNDSLA ARLAVEMKTD LLIVLSDVEG LFDSPPGSDD AKLIDIFYPG DQQSVTFGTK 310 320 330 340 350 360 SRVGMGGMEA KVKAALWALQ GGTSVVIANG THPKVSGHVI TDIVEGKKVG TFFSEVKPAG 370 380 390 400 410 420 PTVEQQGEMA RSGGRMLATL EPEQRAEIIH HLADLLTDQR DEILLANKKD LEEAEGRLAA 430 440 450 460 470 480 PLLKRLSLST SKLNSLAIGL RQIAASSQDS VGRVLRRTRI AKNLELEQVT VPIGVLLVIF 490 500 510 520 530 540 ESRPDCLPQV AALAIASGNG LLLKGGKEAA HSNRILHLLT QEALSIHGVK EAVQLVNTRE 550 560 570 580 590 600 EVEDLCRLDK MIDLIIPRGS SQLVRDIQKA AKGIPVMGHS EGICHMYVDS EASVDKVTRL 610 620 630 640 650 660 VRDSKCEYPA ACNALETLLI HRDLLRTPLF DQIIDMLRVE QVKIHAGPKF ASYLTFSPSE 670 680 690 700 710 720 VKSLRTEYGD LELCIEVVDN VQDAIDHIHK YGSSHTDVIV TEDENTAEFF LQHVDSACVF 730 740 750 760 770 780 WNASTRFSDG YRFGLGAEVG ISTSRIHARG PVGLEGLLTT KWLLRGKDHV VSDFSEHGSL 790 KYLHENLPIP QRNTN
	Isoform Short [UniParc]. Checksum: 550F0B435805C0CA		793	87,089
	10 20 30 40 50 60 MLSQVYRCGF QPFNQHLLPW VKCTTVFRSH CIQPSVIRHV RSWSNIPFIT VPLSRTHGKS 70 80 90 100 110 120 FAHRSELKHA KRIVVKLGSA VVTRGDECGL ALGRLASIVE QVSVLQNQGR EMMLVTSGAV 130 140 150 160 170 180 AFGKQRLRHE ILLSQSVRQA LHSGQNQLKE MAIPVLEARA CAAAGQSGLM ALYEAMFTQY 190 200 210 220 230 240 SICAAQILVT NLDFHDEQKR RNLNGTLHEL LRMNIVPIVN TNDAVVPPAE PNSDLQGVIS 250 260 270 280 290 300 VKDNDSLAAR LAVEMKTDLL IVLSDVEGLF DSPPGSDDAK LIDIFYPGDQ QSVTFGTKSR 310 320 330 340 350 360 VGMGGMEAKV KAALWALQGG TSVVIANGTH PKVSGHVITD IVEGKKVGTF FSEVKPAGPT 370 380 390 400 410 420 VEQQGEMARS GGRMLATLEP EQRAEIIHHL ADLLTDQRDE ILLANKKDLE EAEGRLAAPL 430 440 450 460 470 480 LKRLSLSTSK LNSLAIGLRQ IAASSQDSVG RVLRRTRIAK NLELEQVTVP IGVLLVIFES 490 500 510 520 530 540 RPDCLPQVAA LAIASGNGLL LKGGKEAAHS NRILHLLTQE ALSIHGVKEA VQLVNTREEV 550 560 570 580 590 600 EDLCRLDKMI DLIIPRGSSQ LVRDIQKAAK GIPVMGHSEG ICHMYVDSEA SVDKVTRLVR 610 620 630 640 650 660 DSKCEYPAAC NALETLLIHR DLLRTPLFDQ IIDMLRVEQV KIHAGPKFAS YLTFSPSEVK 670 680 690 700 710 720 SLRTEYGDLE LCIEVVDNVQ DAIDHIHKYG SSHTDVIVTE DENTAEFFLQ HVDSACVFWN 730 740 750 760 770 780 ASTRFSDGYR FGLGAEVGIS TSRIHARGPV GLEGLLTTKW LLRGKDHVVS DFSEHGSLKY 790 LHENLPIPQR NTN

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Database cloning human delta 1-pyrroline-5-carboxylate synthetase (P5CS) cDNA: a bifunctional enzyme catalyzing the first 2 steps in proline biosynthesis." Aral B., Schlenzig J.S., Liu G., Kamoun P. C. R. Acad. Sci. III, Sci. Vie 319:171-178(1996) [PubMed: 8761662] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG). Tissue: Kidney.
[2]	"Molecular enzymology of mammalian delta1-pyrroline-5-carboxylate synthase. Alternative splice donor utilization generates isoforms with different sensitivity to ornithine inhibition." Hu C.A., Lin W.-W., Obie C., Valle D. J. Biol. Chem. 274:6754-6762(1999) [PubMed: 10037775] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS LONG AND SHORT), ENZYME REGULATION. Tissue: Small intestine.
[3]	"The DNA sequence and comparative analysis of human chromosome 10." Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J. , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J. Nature 429:375-381(2004) [PubMed: 15164054] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LONG). Tissue: Brain.
[5]	"Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase." Baumgartner M.R., Hu C.A., Almashanu S., Steel G., Obie C., Aral B., Rabier D., Kamoun P., Saudubray J.-M., Valle D. Hum. Mol. Genet. 9:2853-2858(2000) [PubMed: 11092761] [Abstract] Cited for: VARIANT P5CS DEFICIENCY GLN-84, CHARACTERIZATION OF VARIANT P5CS DEFICIENCY GLN-84.

Cross-references

Sequence databases

EMBLGenBankDDBJ

X94453 mRNA. Translation: CAA64224.1.
U76542 mRNA. Translation: AAD17454.1.
U68758 mRNA. Translation: AAD00169.1.
AL356632 Genomic DNA. Translation: CAI16766.1.
BC117240 mRNA. Translation: AAI17241.1.
BC117242 mRNA. Translation: AAI17243.1.

RefSeq

NP_001017423.1.
NP_002851.2.

UniGene

Hs.500645

3D structure databases

PDBMSD

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2H5G	X-ray	2.25	A/B	352-795	[»]

ModBase

Search...

PTM databases

PhosphoSite

P54886.

Genome annotation databases

Ensembl

ENSG00000059573. Homo sapiens. [Contig view]