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Reviewed, UniProtKB/Swiss-Prot P54886 (P5CS_HUMAN)

Last modified November 25, 2008. Version 92. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (8) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Alternative products · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended 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
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length795 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is not processed.
Protein existenceEvidence 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.

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 keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 795795Delta-1-pyrroline-5-carboxylate synthetase
PRO_0000109769

Regions

Region1 – 361361Glutamate 5-kinase
Region362 – 795434Gamma-glutamyl phosphate reductase

Natural variations

Alternative sequence239 – 2402Missing in isoform Short.
VSP_005215
Natural variant841R → Q in P5CS deficiency; reduction of activity.
VAR_038482

Experimental info

Sequence conflict1261R → T in CAA64224. Ref.1
Sequence conflict2661S → P in CAA64224. Ref.1
Sequence conflict2991T → P in CAA64224. Ref.1
Sequence conflict305 – 3073MGG → NGC in CAA64224. Ref.1
Sequence conflict314 – 3152AA → ST in CAA64224. Ref.1
Sequence conflict487 – 4937LPQVAAL → PTPGGSF in CAA64224. Ref.1

Secondary structure

..................................................................... 795
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform Long [UniParc].

Last modified May 30, 2000. Version 2.
Checksum: 8BF27EF2A8FB2D79

FASTA79587,302
        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 

« Hide

Isoform Short [UniParc].

Checksum: 550F0B435805C0CA
Show »

79387,089

References

« Hide '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. expand/collapse author list , 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

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.
RefSeqNP_001017423.1.
NP_002851.2.
UniGeneHs.500645

3D structure databases

EntryMethodResolution (Å)ChainPositionsPDBsum
2H5GX-ray2.25A/B352-795[»]
ModBaseSearch...

PTM databases

PhosphoSiteP54886.

Genome annotation databases

EnsemblENSG00000059573. Homo sapiens. [Contig view]