P30038 (AL4A1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial
Short name=P5C dehydrogenase
EC=1.5.1.12

Alternative name(s):
Aldehyde dehydrogenase family 4 member A1

Gene names

Name:	ALDH4A1
Synonyms:	ALDH4, P5CDH

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	563 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Irreversible conversion of delta-1-pyrroline-5-carboxylate (P5C), derived either from proline or ornithine, to glutamate. This is a necessary step in the pathway interconnecting the urea and tricarboxylic acid cycles. The preferred substrate is glutamic gamma-semialdehyde, other substrates include succinic, glutaric and adipic semialdehydes.
Catalytic activity	(S)-1-pyrroline-5-carboxylate + NAD(P)+ + 2 H2O = L-glutamate + NAD(P)H.
Pathway	Amino-acid degradation; L-proline degradation into L-glutamate; L-glutamate from L-proline: step 2/2.
Subunit structure	Homodimer.
Subcellular location	Mitochondrion matrix.
Tissue specificity	Highest expression is found in liver followed by skeletal muscle, kidney, heart, brain, placenta, lung and pancreas.
Involvement in disease	Defects in ALDH4A1 are the cause of hyperprolinemia type 2 (HP-2) [MIM:239510]. HP-2 is characterized by the accumulation of delta-1-pyrroline-5-carboxylate (P5C) and proline. The disorder may be causally related to neurologic manifestations, including seizures and mental retardation. Ref.12
Sequence similarities	Belongs to the aldehyde dehydrogenase family.

Ontologies

Keywords
Biological process	Proline metabolism
Cellular component	Mitochondrion
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Transit peptide
Ligand	NAD
Molecular function	Oxidoreductase
PTM	Acetylation Phosphoprotein
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	proline biosynthetic process Inferred from electronic annotation. Source: InterPro proline catabolic process Traceable author statement. Source: Reactome
Cellular component	mitochondrial matrix Traceable author statement. Source: Reactome
Molecular function	1-pyrroline-5-carboxylate dehydrogenase activity Inferred from experiment. Source: Reactome aldehyde dehydrogenase (NAD) activity Traceable author statement. Source: ProtInc electron carrier activity Traceable author statement Ref.1. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Transit peptide	1 – 24	24	Mitochondrion Ref.8
	Chain	25 – 563	539	Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial		PRO_0000007173
Regions
	Nucleotide binding	296 – 301	6	NAD By similarity
Sites
	Active site	314	1	Proton acceptor By similarity
	Active site	348	1	Nucleophile By similarity
	Site	211	1	Transition state stabilizer By similarity
Amino acid modifications
	Modified residue	99	1	N6-acetyllysine By similarity
	Modified residue	114	1	N6-acetyllysine By similarity
	Modified residue	402	1	N6-acetyllysine By similarity
	Modified residue	505	1	Phosphotyrosine Ref.10
Natural variations
	Natural variant	16	1	P → L in allele ALDH4A1*4. Ref.12		VAR_002259
	Natural variant	352	1	S → L in HP-2; allele ALDH4A1*3. Ref.12		VAR_002260
	Natural variant	470	1	V → I. Ref.2 Ref.6 Corresponds to variant rs2230709 [ dbSNP | Ensembl ].		VAR_029337
	Natural variant	473	1	T → A. Corresponds to variant rs6695033 [ dbSNP | Ensembl ].		VAR_048903
Experimental info
	Sequence conflict	68	1	V → M in AAC50501. Ref.1
	Sequence conflict	68	1	V → M in AAC50500. Ref.1
	Sequence conflict	189 – 191	3	PPS → LPY AA sequence Ref.9
	Sequence conflict	189	1	P → L AA sequence Ref.7
	Sequence conflict	226	1	M → I in BAD96206. Ref.3
	Sequence conflict	271	1	D → E AA sequence Ref.7
	Sequence conflict	271	1	D → E AA sequence Ref.9
	Sequence conflict	354	1	L → K AA sequence Ref.9
	Sequence conflict	376	1	K → R in BAD96206. Ref.3
	Sequence conflict	524 – 526	3	RAS → GSA AA sequence Ref.9

Sequences

	Sequence		Length	Mass (Da)
	P30038 [UniParc]. Last modified February 1, 2005. Version 3. Checksum: 4D964771B7DB5FFD	FASTA	563	61,719
	10 20 30 40 50 60 MLLPAPALRR ALLSRPWTGA GLRWKHTSSL KVANEPVLAF TQGSPERDAL QKALKDLKGR 70 80 90 100 110 120 MEAIPCVVGD EEVWTSDVQY QVSPFNHGHK VAKFCYADKS LLNKAIEAAL AARKEWDLKP 130 140 150 160 170 180 IADRAQIFLK AADMLSGPRR AEILAKTMVG QGKTVIQAEI DAAAELIDFF RFNAKYAVEL 190 200 210 220 230 240 EGQQPISVPP STNSTVYRGL EGFVAAISPF NFTAIGGNLA GAPALMGNVV LWKPSDTAML 250 260 270 280 290 300 ASYAVYRILR EAGLPPNIIQ FVPADGPLFG DTVTSSEHLC GINFTGSVPT FKHLWKQVAQ 310 320 330 340 350 360 NLDRFHTFPR LAGECGGKNF HFVHRSADVE SVVSGTLRSA FEYGGQKCSA CSRLYVPHSL 370 380 390 400 410 420 WPQIKGRLLE EHSRIKVGDP AEDFGTFFSA VIDAKSFARI KKWLEHARSS PSLTILAGGK 430 440 450 460 470 480 CDDSVGYFVE PCIVESKDPQ EPIMKEEIFG PVLSVYVYPD DKYKETLQLV DSTTSYGLTG 490 500 510 520 530 540 AVFSQDKDVV QEATKVLRNA AGNFYINDKS TGSIVGQQPF GGARASGTND KPGGPHYILR 550 560 WTSPQVIKET HKPLGDWSYA YMQ

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning, characterization, and expression of cDNAs encoding human delta 1-pyrroline-5-carboxylate dehydrogenase." Hu C.-A., Lin W.-W., Valle D. J. Biol. Chem. 271:9795-9800(1996) [PubMed: 8621661] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Kidney and Retina.
[2]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT ILE-470. Tissue: Hippocampus.
[3]	Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S. Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Adipose tissue.
[4]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed: 16710414] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"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], VARIANT ILE-470. Tissue: Lung and Placenta.
[7]	"Human liver glutamic gamma-semialdehyde dehydrogenase: structural relationship to the yeast enzyme." Hempel J., Eckey R., Berie D., Romovacek H., Agarwal D.P., Goedde H.W. Comp. Biochem. Physiol. 102B:791-793(1992) [PubMed: 1395511] [Abstract] Cited for: PARTIAL PROTEIN SEQUENCE. Tissue: Liver.
[8]	"Human liver protein map: a reference database established by microsequencing and gel comparison." Hochstrasser D.F., Frutiger S., Paquet N., Bairoch A., Ravier F., Pasquali C., Sanchez J.-C., Tissot J.-D., Bjellqvist B., Vargas R., Appel R.D., Hughes G.J. Electrophoresis 13:992-1001(1992) [PubMed: 1286669] [Abstract] Cited for: PROTEIN SEQUENCE OF 25-35. Tissue: Liver.
[9]	"Human liver high Km aldehyde dehydrogenase (ALDH4): properties and structural relationship to the glutamic gamma-semialdehyde dehydrogenase." Agarwal D.P., Eckey R., Hempel J., Goedde H.W. Adv. Exp. Med. Biol. 328:191-197(1993) [PubMed: 8493898] [Abstract] Cited for: PROTEIN SEQUENCE OF 94-99; 105-113; 125-139; 176-191; 251-273; 339-347; 354-365 AND 510-526. Tissue: Liver.
[10]	"Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer." Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J., Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L., Mitchell J., Wetzel R., Macneill J., Ren J.M. , Yuan J., Bakalarski C.E., Villen J., Kornhauser J.M., Smith B., Li D., Zhou X., Gygi S.P., Gu T.-L., Polakiewicz R.D., Rush J., Comb M.J. Cell 131:1190-1203(2007) [PubMed: 18083107] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-505, MASS SPECTROMETRY. Tissue: Lung carcinoma.
[11]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed: 21269460] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[12]	"Mutations in the Delta1-pyrroline 5-carboxylate dehydrogenase gene cause type II hyperprolinemia." Geraghty M.T., Vaughn D., Nicholson A.J., Lin W.-W., Jimenez-Sanchez G., Obie C., Flynn M.P., Valle D., Hu C.-A.A. Hum. Mol. Genet. 7:1411-1415(1998) [PubMed: 9700195] [Abstract] Cited for: VARIANT HP-2 LEU-352, VARIANT LEU-16.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	U24267 mRNA. Translation: AAC50501.1. U24266 mRNA. Translation: AAC50500.1. AK289972 mRNA. Translation: BAF82661.1. AK222486 mRNA. Translation: BAD96206.1. AL080251, AL954340 Genomic DNA. Translation: CAI23417.1. AL954340, AL080251 Genomic DNA. Translation: CAI39493.1. CH471134 Genomic DNA. Translation: EAW94858.1. BC007581 mRNA. Translation: AAH07581.1. BC023600 mRNA. Translation: AAH23600.1.
IPI	IPI00217871.
RefSeq	NP_001154976.1. NM_001161504.1. NP_003739.2. NM_003748.3. NP_733844.1. NM_170726.2.
UniGene	Hs.77448.
3D structure databases
ProteinModelPortal	P30038.
SMR	P30038. Positions 29-551.
ModBase	Search...
Protein-protein interaction databases
IntAct	P30038. 1 interaction.
STRING	P30038.
PTM databases
PhosphoSite	P30038.
Polymorphism databases
DMDM	62511241.
2D gel databases
SWISS-2DPAGE	P30038.
OGP	P30038.
Proteomic databases
PRIDE	P30038.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000290597; ENSP00000290597; ENSG00000159423. ENST00000375341; ENSP00000364490; ENSG00000159423.
GeneID	8659.
KEGG	hsa:8659.
UCSC	uc001bbb.1. human.
Organism-specific databases
CTD	8659.
GeneCards	GC01M019197.
H-InvDB	HIX0022349.
HGNC	HGNC:406. ALDH4A1.
HPA	CAB004645. HPA006401.
MIM	239510. phenotype. 606811. gene.
neXtProt	NX_P30038.
Orphanet	79101. Hyperprolinemia type II.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG05273.
GeneTree	ENSGT00560000077335.
HOVERGEN	HBG050484.
InParanoid	P30038.
OMA	PQSIKET.
OrthoDB	EOG4ZCT3Q.
PhylomeDB	P30038.
Enzyme and pathway databases
BioCyc	MetaCyc:MONOMER-11403.
Reactome	REACT_111217. Metabolism.
Gene expression databases
ArrayExpress	P30038.
Bgee	P30038.
CleanEx	HS_ALDH4A1.
Genevestigator	P30038.
GermOnline	ENSG00000159423. Homo sapiens.
Family and domain databases
InterPro	IPR016161. Ald_DH/histidinol_DH. IPR016163. Ald_DH_C. IPR016160. Ald_DH_CS. IPR016162. Ald_DH_N. IPR015590. Aldehyde_DH_dom. IPR005931. Delta1-pyrroline-5-COlate_DH-1. [Graphical view]
Gene3D	G3DSA:3.40.309.10. Aldehyde_dehydrogenase_C. 1 hit. G3DSA:3.40.605.10. Aldehyde_dehydrogenase_N. 1 hit.
KO	K00294.
Pfam	PF00171. Aldedh. 1 hit. [Graphical view]
SUPFAM	SSF53720. Aldehyde_DH/Histidinol_DH. 1 hit.
TIGRFAMs	TIGR01236. D1pyr5carbox1. 1 hit.
PROSITE	PS00070. ALDEHYDE_DEHYDR_CYS. 1 hit. PS00687. ALDEHYDE_DEHYDR_GLU. 1 hit. [Graphical view]
ProtoNet	Search...
Other
DrugBank	DB00157. NADH.
NextBio	32473.
SOURCE	Search...

Entry information

Entry name

AL4A1_HUMAN

Accession

Primary (citable) accession number: P30038
Secondary accession number(s): A8K1Q7 , Q16882, Q53HU4, Q5JNV6, Q8IZ38, Q96IF0, Q9UDI6

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 1, 1993
Last sequence update:	February 1, 2005
Last modified:	January 25, 2012
This is version 129 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.