P15428 (PGDH_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
15-hydroxyprostaglandin dehydrogenase [NAD+]
Short name=15-PGDH
EC=1.1.1.141

Alternative name(s):
Prostaglandin dehydrogenase 1

Gene names

Name:	HPGD
Synonyms:	PGDH1

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	266 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Prostaglandin inactivation. Contributes to the regulation of events that are under the control of prostaglandin levels. Catalyzes the NAD-dependent dehydrogenation of lipoxin A4 to form 15-oxo-lipoxin A4. Inhibits in vivo proliferation of colon cancer cells. Ref.8 Ref.10 Ref.11
Catalytic activity	(5Z,13E,15S)-11-alpha,15-dihydroxy-9-oxoprost-5,13-dienoate + NAD+ = (5Z,13E)-11-alpha-hydroxy-9,15-dioxoprost-5,13-dienoate + NADH.
Subunit structure	Homodimer.
Subcellular location	Cytoplasm.
Tissue specificity	Detected in colon epithelium (at protein level). Ref.10
Induction	Down-regulated by cortisol, dexamethasone and betamethasone. Down-regulated in colon cancer. Up-regulated by TGFB1. Ref.9 Ref.10
Involvement in disease	Defects in HPGD are the cause of primary hypertrophic osteoathropathy autosomal recessive (PHOAR) [MIM:259100]; also known as pachydermoperiostosis autosomal recessive. Primary hypertrophic osteoarthropathy is characterized by digital clubbing, osterarthropathy, variable features of pachydermia, delayed closure of the fontanels, and congenital heart disease. Ref.13 Defects in HPGD are the cause of cranioosteoarthropathy (COA) [MIM:259100]. Clinical features include infantile onset of swelling of the joints, digital clubbing, hyperhidrosis, delayed closure of the fontanels, periostosis, and variable patent ductus arteriosus. Pachydermia is not a prominent feature. Ref.13 Defects in HPGD are a cause of isolated congenital nail clubbing (ICNC) [MIM:119900]; also called clubbing of digits or hereditary acropachy. ICNC is a rare genodermatosis characterized by enlargement of the nail plate and terminal segments of the fingers and toes, resulting from proliferation of the connective tissues between the nail matrix and the distal phalanx. It is usually symmetrical and bilateral (in some cases unilateral). In nail clubbing usually the distal end of the nail matrix is relatively high compared to the proximal end, while the nail plate is complete but its dimensions and diameter more or less vary in comparison to normal. There may be different fingers and toes involved to varying degrees. Some fingers or toes are spared, but the thumbs are almost always involved. Ref.16
Sequence similarities	Belongs to the short-chain dehydrogenases/reductases (SDR) family.
Biophysicochemical properties	Kinetic parameters: KM=3.4 µM for prostaglandin E2 Ref.11 KM=38 µM for NAD

Ontologies

Keywords
Biological process	Fatty acid metabolism Lipid metabolism Prostaglandin metabolism
Cellular component	Cytoplasm
Coding sequence diversity	Polymorphism
Disease	Disease mutation Tumor suppressor
Ligand	NAD
Molecular function	Oxidoreductase
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	ductus arteriosus closure Inferred from sequence or structural similarity. Source: UniProtKB female pregnancy Inferred from direct assay. Source: UniProtKB lipoxygenase pathway Traceable author statement. Source: UniProtKB negative regulation of cell cycle Inferred from direct assay Ref.10. Source: UniProtKB ovulation Inferred from sequence or structural similarity. Source: UniProtKB parturition Inferred from direct assay. Source: UniProtKB prostaglandin metabolic process Inferred from direct assay Ref.11. Source: UniProtKB thrombin receptor signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB transforming growth factor beta receptor signaling pathway Inferred from direct assay Ref.10. Source: UniProtKB
Cellular component	cytosol Non-traceable author statement. Source: UniProtKB nucleus Inferred from direct assay. Source: HPA
Molecular function	15-hydroxyprostaglandin dehydrogenase (NAD+) activity Inferred from direct assay Ref.11Ref.7. Source: UniProtKB NAD+ binding Inferred from direct assay Ref.11. Source: UniProtKB prostaglandin E receptor activity Inferred from direct assay. Source: UniProtKB protein homodimerization activity Traceable author statement Ref.7. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 266

266

15-hydroxyprostaglandin dehydrogenase [NAD+]

PRO_0000054744

Regions

Nucleotide binding

12 – 20

9

NAD

Nucleotide binding

36 – 37

2

NAD

Nucleotide binding

63 – 65

3

NAD

Nucleotide binding

151 – 155

5

NAD

Nucleotide binding

186 – 188

3

NAD

Sites

Active site

151

1

Proton acceptor

Binding site

91

1

NAD; via carbonyl oxygen

Binding site

138

1

Substrate Probable

Binding site

148

1

Substrate Probable

Natural variations

Natural variant

140

1

A → P in COA; inactive. Ref.13

VAR_046209

Natural variant

193

1

S → P in ICNC. Ref.16

VAR_060792

Natural variant

217

1

Y → C.

VAR_006972

Experimental info

Mutagenesis

148

1

Q → A: Loss of activity. Ref.11

Mutagenesis

148

1

Q → E, H or N: Reduced affinity for NAD and prostaglandin E2. Ref.11

Mutagenesis

151

1

Y → A: Loss of activity. Ref.7

Sequence conflict

50

1

D → H in AAA89175. Ref.2

Sequence conflict

50

1

D → H in AAA89174. Ref.2

Secondary structure

1

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266

Helix Strand Turn

Details...

Beta strand

7 – 11

5

Turn

12 – 14

3

Helix

16 – 27

12

Beta strand

31 – 37

7

Helix

39 – 49

11

Turn

50 – 52

3

Helix

55 – 57

3

Beta strand

58 – 62

5

Helix

68 – 82

15

Beta strand

87 – 90

4

Beta strand

97 – 99

3

Helix

100 – 107

8

Helix

109 – 122

14

Helix

124 – 126

3

Beta strand

131 – 136

6

Helix

139 – 141

3

Helix

149 – 172

24

Beta strand

176 – 184

9

Beta strand

186 – 188

3

Helix

189 – 192

4

Helix

193 – 195

3

Helix

197 – 200

4

Helix

201 – 206

6

Helix

207 – 217

11

Helix

222 – 234

13

Beta strand

242 – 246

5

Turn

247 – 249

3

Beta strand

250 – 253

4

Sequences

	Sequence		Length	Mass (Da)
	P15428 [UniParc]. Last modified April 1, 1990. Version 1. Checksum: B860D2DE80E49514	FASTA	266	28,977
	10 20 30 40 50 60 MHVNGKVALV TGAAQGIGRA FAEALLLKGA KVALVDWNLE AGVQCKAALD EQFEPQKTLF 70 80 90 100 110 120 IQCDVADQQQ LRDTFRKVVD HFGRLDILVN NAGVNNEKNW EKTLQINLVS VISGTYLGLD 130 140 150 160 170 180 YMSKQNGGEG GIIINMSSLA GLMPVAQQPV YCASKHGIVG FTRSAALAAN LMNSGVRLNA 190 200 210 220 230 240 ICPGFVNTAI LESIEKEENM GQYIEYKDHI KDMIKYYGIL DPPLIANGLI TLIEDDALNG 250 260 AIMKITTSKG IHFQDYDTTP FQAKTQ

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Purification and structural characterization of placental NAD(+)-linked 15-hydroxyprostaglandin dehydrogenase. The primary structure reveals the enzyme to belong to the short-chain alcohol dehydrogenase family." Krook M., Marekov L., Joernvall H. Biochemistry 29:738-743(1990) [PubMed: 2337593] [Abstract] Cited for: PROTEIN SEQUENCE. Tissue: Placenta.
[2]	"Cloning and sequence analysis of the cDNA for human placental NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase." Ensor C.M., Yang J.Y., Okita R.T., Tai H.-H. J. Biol. Chem. 265:14888-14891(1990) [PubMed: 1697582] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Placenta.
[3]	"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]. Tissue: Placenta.
[4]	SeattleSNPs variation discovery resource Submitted (AUG-2006) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [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 (SEP-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]. Tissue: Pancreas.
[7]	"Site-directed mutagenesis of the conserved tyrosine 151 of human placental NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase yields a catalytically inactive enzyme." Ensor C.M., Tai H.-H. Biochem. Biophys. Res. Commun. 176:840-845(1991) [PubMed: 2025296] [Abstract] Cited for: MUTAGENESIS OF TYR-151.
[8]	"Oxidoreductases in lipoxin A4 metabolic inactivation: a novel role for 15-onoprostaglandin 13-reductase/leukotriene B4 12-hydroxydehydrogenase in inflammation." Clish C.B., Levy B.D., Chiang N., Tai H.-H., Serhan C.N. J. Biol. Chem. 275:25372-25380(2000) [PubMed: 10837478] [Abstract] Cited for: FUNCTION.
[9]	"Mechanism of cortisol/progesterone antagonism in the regulation of 15-hydroxyprostaglandin dehydrogenase activity and messenger ribonucleic acid levels in human chorion and placental trophoblast cells at term." Patel F.A., Funder J.W., Challis J.R.G. J. Clin. Endocrinol. Metab. 88:2922-2933(2003) [PubMed: 12788907] [Abstract] Cited for: INDUCTION.
[10]	"15-Hydroxyprostaglandin dehydrogenase, a COX-2 oncogene antagonist, is a TGF-beta-induced suppressor of human gastrointestinal cancers." Yan M., Rerko R.M., Platzer P., Dawson D., Willis J., Tong M., Lawrence E., Lutterbaugh J., Lu S., Willson J.K.V., Luo G., Hensold J., Tai H.-H., Wilson K., Markowitz S.D. Proc. Natl. Acad. Sci. U.S.A. 101:17468-17473(2004) [PubMed: 15574495] [Abstract] Cited for: FUNCTION, INDUCTION, TISSUE SPECIFICITY.
[11]	"Role of glutamine 148 of human 15-hydroxyprostaglandin dehydrogenase in catalytic oxidation of prostaglandin E2." Cho H., Huang L., Hamza A., Gao D., Zhan C.-G., Tai H.-H. Bioorg. Med. Chem. 14:6486-6491(2006) [PubMed: 16828555] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF GLN-148, BIOPHYSICOCHEMICAL PROPERTIES, 3D-STRUCTURE MODELING.
[12]	"Three-dimensional model of NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase and relationships to the NADP(+)-dependent enzyme (carbonyl reductase)." Krook M., Ghosh D., Duax W.L., Joernvall H. FEBS Lett. 322:139-142(1993) [PubMed: 8482380] [Abstract] Cited for: 3D-STRUCTURE MODELING.
[13]	"Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy." Uppal S., Diggle C.P., Carr I.M., Fishwick C.W.G., Ahmed M., Ibrahim G.H., Helliwell P.S., Latos-Bielenska A., Phillips S.E.V., Markham A.F., Bennett C.P., Bonthron D.T. Nat. Genet. 40:789-793(2008) [PubMed: 18500342] [Abstract] Cited for: INVOLVEMENT IN PHOAR, VARIANT COA PRO-140, CHARACTERIZATION OF VARIANT COA PRO-140.
[14]	Erratum Uppal S., Diggle C.P., Carr I.M., Fishwick C.W.G., Ahmed M., Ibrahim G.H., Helliwell P.S., Latos-Bielenska A., Phillips S.E.V., Markham A.F., Bennett C.P., Bonthron D.T. Nat. Genet. 40:927-927(2008)
[15]	"Crystal structure of 15-hydroxyprostaglandin dehydrogenase type 1, complexed with NAD+." Structural genomics consortium (SGC) Submitted (FEB-2009) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 3-256 IN COMPLEX WITH NAD.
[16]	"Mutation in the HPGD gene encoding NAD+ dependent 15-hydroxyprostaglandin dehydrogenase underlies isolated congenital nail clubbing (ICNC)." Tariq M., Azeem Z., Ali G., Chishti M.S., Ahmad W. J. Med. Genet. 46:14-20(2009) [PubMed: 18805827] [Abstract] Cited for: VARIANT ICNC PRO-193.
+	Additional computationally mapped references.

Web resources

SeattleSNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L76465 mRNA. Translation: AAA89175.1.
J05594 mRNA. Translation: AAA89174.1.
AK314624 mRNA. Translation: BAG37190.1.
DQ903072 Genomic DNA. Translation: ABI75347.1.
CH471056 Genomic DNA. Translation: EAX04734.1.
CH471056 Genomic DNA. Translation: EAX04736.1.
BC018986 mRNA. Translation: AAH18986.1.

IPI

IPI00305286.

PIR

A35802.

RefSeq

NP_000851.2. NM_000860.4.
NP_001139288.1. NM_001145816.1.

UniGene

Hs.596913.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2GDZ	X-ray	1.65	A	3-256	[»]

ProteinModelPortal

P15428.

SMR

P15428. Positions 3-258.

ModBase

Search...

Protein-protein interaction databases

STRING

P15428.

Polymorphism databases

DMDM

129889.

2D gel databases

SWISS-2DPAGE

P15428.

Siena-2DPAGE

P15428.

Proteomic databases

PRIDE

P15428.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000296522; ENSP00000296522; ENSG00000164120.

GeneID

3248.

KEGG

hsa:3248.

UCSC

uc003itu.1. human.

Organism-specific databases

CTD

3248.

GeneCards

GC04M175411.

H-InvDB

HIX0004645.

HGNC

HGNC:5154. HPGD.

HPA

HPA004919.
HPA005679.

MIM

119900. phenotype.
259100. phenotype.
601688. gene.

neXtProt

NX_P15428.

Orphanet

1525. Cranio-osteoarthropathy.
217059. Isolated congenital digital clubbing.
2796. Pachydermoperiostosis.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

HBG750976.

HOVERGEN

HBG107379.

InParanoid

P15428.

OMA

DPSMIAN.

OrthoDB

EOG4R23VH.

PhylomeDB

P15428.

Gene expression databases

ArrayExpress

P15428.

Bgee

P15428.

CleanEx

HS_HPGD.

Genevestigator

P15428.

GermOnline

ENSG00000164120. Homo sapiens.

Family and domain databases

InterPro

IPR002198. DH_sc/Rdtase_SDR.
IPR002347. Glc/ribitol_DH.
IPR016040. NAD(P)-bd_dom.
IPR020904. Sc_DH/Rdtase_CS.
[Graphical view]

Gene3D

G3DSA:3.40.50.720. NAD(P)-bd. 1 hit.

KO

K00069.

Pfam

PF00106. adh_short. 1 hit.
[Graphical view]

PRINTS

PR00081. GDHRDH.
PR00080. SDRFAMILY.

PROSITE

PS00061. ADH_SHORT. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

DrugBank

DB00157. NADH.

NextBio

12913.

SOURCE

Search...

Entry information

Entry name

PGDH_HUMAN

Accession

Primary (citable) accession number: P15428
Secondary accession number(s): D3DP43, Q06F08

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 1, 1990
Last sequence update:	April 1, 1990
Last modified:	January 25, 2012
This is version 123 of the entry and version 1 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.