Reviewed, UniProtKB/Swiss-Prot P51659 (DHB4_HUMAN)

Names and origin

Protein names

Recommended name:
    Peroxisomal multifunctional enzyme type 2
      Short name=MFE-2
Alternative name(s):
    D-bifunctional protein
      Short name=DBP
    17-beta-hydroxysteroid dehydrogenase 4
      Short name=17-beta-HSD 4
Including the following 2 domains:
    1- Recommended name:
            3-hydroxyacyl-CoA dehydrogenase
              EC=1.1.1.35
    2- Recommended name:
            3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholest-24-enoyl-CoA hydratase
              EC=4.2.1.107

Gene names

Name:	HSD17B4
Synonyms:	EDH17B4

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	736 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	Bifunctional enzyme acting on the peroxisomal beta-oxidation pathway for fatty acids. Catalyzes the formation of 3-ketoacyl-CoA intermediates from both straight-chain and 2-methyl-branched-chain fatty acids. Ref.2
Catalytic activity	(24R,25R)-3-alpha,7-alpha,12-alpha,24-tetrahydroxy-5-beta-cholestanoyl-CoA = (24E)-3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholest-24-enoyl-CoA + H2O. (S)-3-hydroxyacyl-CoA + NAD+ = 3-oxoacyl-CoA + NADH.
Pathway	Lipid metabolism; fatty acid beta-oxidation.
Subcellular location	Peroxisome.
Tissue specificity	Present in many tissues with highest concentrations in liver, heart, prostate and testis.
Involvement in disease	Defects in HSD17B4 are a cause of D-bifunctional protein deficiency (DBPD) [MIM:261515]. DBPD is a disorder of peroxisomal fatty acid beta-oxidation. Ref.11
Sequence similarities	Belongs to the short-chain dehydrogenases/reductases (SDR) family. Contains 1 SCP2 domain.

Ontologies

Keywords
Biological process	Fatty acid metabolism Lipid metabolism
Cellular component	Peroxisome
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Ligand	NAD
Molecular function	Isomerase Lyase Oxidoreductase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	fatty acid beta-oxidation using acyl-CoA oxidase Inferred from Experiment. Source: Reactome oxidation reduction Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	peroxisomal matrix Ref.5 Inferred from Experiment. Source: Reactome
Molecular function	3-hydroxyacyl-CoA dehydrogenase activity Ref.5 Inferred from Experiment. Source: Reactome 3alpha,7alpha,12alpha-trihydroxy-5beta-cholest-24-enoyl-CoA hydratase activity Ref.5 Inferred from Experiment. Source: Reactome estradiol 17-beta-dehydrogenase activity Ref.3 Traceable author statement. Source: ProtInc isomerase activity Inferred from electronic annotation. Source: UniProtKB-KW protein binding Inferred from physical interaction. Source: IntAct sterol carrier activity Ref.3 Traceable author statement. Source: ProtInc sterol transporter activity Ref.1 Traceable author statement. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
NDRG1	Q92597	1	EBI-358398,EBI-716486

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed By similarity

Chain

2 – 736

735

Peroxisomal multifunctional enzyme type 2

PRO_0000054583

Regions

Domain

624 – 736

113

SCP2

Nucleotide binding

13 – 37

25

NAD By similarity

Nucleotide binding

75 – 76

2

NAD

Nucleotide binding

164 – 168

5

NAD

Nucleotide binding

196 – 199

4

NAD

Region

2 – 305

304

3-hydroxyacyl-CoA dehydrogenase

Region

322 – 622

301

3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholest-24-enoyl-CoA hydratase

Sites

Active site

164

1

Proton acceptor By similarity

Binding site

21

1

NAD; via amide nitrogen

Binding site

40

1

NAD

Binding site

99

1

NAD; via carbonyl oxygen

Binding site

151

1

Substrate By similarity

Binding site

706

1

Substrate

Binding site

724

1

Substrate

Amino acid modifications

Modified residue

3

1

Phosphoserine By similarity

Modified residue

265

1

Phosphothreonine Ref.6

Modified residue

309

1

Phosphoserine By similarity

Modified residue

565

1

N6-acetyllysine Ref.8

Modified residue

663

1

N6-acetyllysine By similarity

Modified residue

669

1

N6-acetyllysine Ref.8

Modified residue

707

1

N6-acetyllysine Ref.8

Natural variations

Natural variant

16

1

G → S in DBPD. Ref.11

VAR_037576

Natural variant

90

1

F → L: dbSNP rs28943588.

VAR_052309

Natural variant

106

1

R → H: dbSNP rs25640.

VAR_014872

Natural variant

140

1

K → N: dbSNP rs28943589.

VAR_052310

Natural variant

292

1

T → S: dbSNP rs1143650.

VAR_024625

Natural variant

427

1

A → V: dbSNP rs28943590.

VAR_052311

Natural variant

491

1

A → T: dbSNP rs28943591.

VAR_052312

Natural variant

511

1

W → R: dbSNP rs11539471.

VAR_014873

Natural variant

559

1

I → V: dbSNP rs11205.

VAR_014874

Natural variant

606

1

A → S: dbSNP rs15228.

VAR_052313

Natural variant

687

1

T → I: dbSNP rs28943592.

VAR_052314

Natural variant

728

1

M → V: dbSNP rs28943594.

VAR_052315

Secondary structure

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736

Helix Strand Turn

Details...

Beta strand

11 – 14

4

Turn

15 – 18

4

Helix

20 – 31

12

Beta strand

35 – 39

5

Helix

53 – 64

12

Beta strand

68 – 72

5

Helix

76 – 78

3

Helix

79 – 90

12

Beta strand

95 – 98

4

Helix

108 – 110

3

Helix

113 – 141

29

Beta strand

144 – 149

6

Helix

152 – 156

5

Helix

162 – 182

21

Helix

183 – 185

3

Beta strand

187 – 194

8

Turn

199 – 204

6

Helix

207 – 212

6

Helix

215 – 217

3

Helix

219 – 225

7

Beta strand

236 – 240

5

Beta strand

243 – 251

9

Helix

266 – 271

6

Helix

273 – 277

5

Helix

288 – 303

16

Beta strand

335 – 339

5

Helix

341 – 350

10

Helix

358 – 360

3

Helix

361 – 364

4

Helix

375 – 377

3

Helix

378 – 381

4

Helix

383 – 385

3

Beta strand

405 – 415

11

Beta strand

419 – 432

14

Beta strand

440 – 462

23

Beta strand

490 – 496

7

Helix

501 – 505

5

Helix

506 – 508

3

Helix

513 – 515

3

Helix

518 – 522

5

Turn

523 – 525

3

Helix

533 – 548

16

Helix

553 – 555

3

Beta strand

556 – 563

8

Beta strand

572 – 580

9

Beta strand

583 – 590

8

Turn

591 – 593

3

Beta strand

596 – 605

10

Helix

624 – 646

23

Beta strand

648 – 670

23

Beta strand

674 – 679

6

Beta strand

685 – 691

7

Helix

692 – 699

8

Helix

705 – 710

6

Beta strand

713 – 719

7

Helix

720 – 733

14

Sequences

	Sequence		Length	Mass (Da)
	P51659-1 [UniParc]. Last modified January 23, 2007. Version 3. Checksum: 7B11E02483328BCE	FASTA	736	79,686
	10 20 30 40 50 60 MGSPLRFDGR VVLVTGAGAG LGRAYALAFA ERGALVVVND LGGDFKGVGK GSLAADKVVE 70 80 90 100 110 120 EIRRRGGKAV ANYDSVEEGE KVVKTALDAF GRIDVVVNNA GILRDRSFAR ISDEDWDIIH 130 140 150 160 170 180 RVHLRGSFQV TRAAWEHMKK QKYGRIIMTS SASGIYGNFG QANYSAAKLG LLGLANSLAI 190 200 210 220 230 240 EGRKSNIHCN TIAPNAGSRM TQTVMPEDLV EALKPEYVAP LVLWLCHESC EENGGLFEVG 250 260 270 280 290 300 AGWIGKLRWE RTLGAIVRQK NHPMTPEAVK ANWKKICDFE NASKPQSIQE STGSIIEVLS 310 320 330 340 350 360 KIDSEGGVSA NHTSRATSTA TSGFAGAIGQ KLPPFSYAYT ELEAIMYALG VGASIKDPKD 370 380 390 400 410 420 LKFIYEGSSD FSCLPTFGVI IGQKSMMGGG LAEIPGLSIN FAKVLHGEQY LELYKPLPRA 430 440 450 460 470 480 GKLKCEAVVA DVLDKGSGVV IIMDVYSYSE KELICHNQFS LFLVGSGGFG GKRTSDKVKV 490 500 510 520 530 540 AVAIPNRPPD AVLTDTTSLN QAALYRLSGD WNPLHIDPNF ASLAGFDKPI LHGLCTFGFS 550 560 570 580 590 600 ARRVLQQFAD NDVSRFKAIK ARFAKPVYPG QTLQTEMWKE GNRIHFQTKV QETGDIVISN 610 620 630 640 650 660 AYVDLAPTSG TSAKTPSEGG KLQSTFVFEE IGRRLKDIGP EVVKKVNAVF EWHITKGGNI 670 680 690 700 710 720 GAKWTIDLKS GSGKVYQGPA KGAADTTIIL SDEDFMEVVL GKLDPQKAFF SGRLKARGNI 730 MLSQKLQMIL KDYAKL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning of a novel widely expressed human 80 kDa 17 beta-hydroxysteroid dehydrogenase IV." Adamski J., Normand T., Leenders F., Monte D., Begue A., Stehelin D., Jungblut P.W., de Launoit Y. Biochem. J. 311:437-443(1995) [PubMed: 7487879] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Liver.
[2]	"Structure of D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein." Jiang L.L., Miyazawa S., Souri M., Hashimoto T. J. Biochem. 121:364-369(1997) [PubMed: 9089413] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION.
[3]	"Structure of the gene for the human 17beta-hydroxysteroid dehydrogenase type IV." Leenders F., Dolez V., Begue A., Moller G., Gloeckner J.C., de Launoit Y., Adamski J. Mamm. Genome 9:1036-1041(1998) [PubMed: 9880674] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [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]. Tissue: Brain.
[5]	"Purification and properties of human D-3-hydroxyacyl-CoA dehydratase: medium-chain enoyl-CoA hydratase is D-3-hydroxyacyl-CoA dehydratase." Jiang L.L., Kobayashi A., Matsuura H., Fukushima H., Hashimoto T. J. Biochem. 120:624-632(1996) [PubMed: 8902629] [Abstract] Cited for: CHARACTERIZATION.
[6]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-265, MASS SPECTROMETRY.
[7]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[8]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed: 19608861] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-565; LYS-669 AND LYS-707, MASS SPECTROMETRY.
[9]	"Crystal structure of the liganded SCP-2-like domain of human peroxisomal multifunctional enzyme type 2 at 1.75 A resolution." Haapalainen A.M., van Aalten D.M., Merilaeinen G., Jalonen J.E., Pirilae P., Wierenga R.K., Hiltunen J.K., Glumoff T. J. Mol. Biol. 313:1127-1138(2001) [PubMed: 11700068] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 618-736 IN COMPLEX WITH LIGAND.
[10]	"Crystal structure of 2-enoyl-CoA hydratase 2 from human peroxisomal multifunctional enzyme type 2." Koski K.M., Haapalainen A.M., Hiltunen J.K., Glumoff T. J. Mol. Biol. 345:1157-1169(2005) [PubMed: 15644212] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 320-614.
[11]	"Peroxisomal D-hydroxyacyl-CoA dehydrogenase deficiency: resolution of the enzyme defect and its molecular basis in bifunctional protein deficiency." van Grunsven E.G., van Berkel E., Ijlst L., Vreken P., de Klerk J.B.C., Adamski J., Lemonde H., Clayton P.T., Cuebas D.A., Wanders R.J.A. Proc. Natl. Acad. Sci. U.S.A. 95:2128-2133(1998) [PubMed: 9482850] [Abstract] Cited for: VARIANT DBPD SER-16.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBLGenBankDDBJ

X87176 mRNA. Translation: CAA60643.1.
AF057740 , AF057720, AF057721, AF057722, AF057723, AF057724, AF057725, AF057726, AF057727, AF057728, AF057729, AF057730, AF057731, AF057732, AF057733, AF057734, AF057735, AF057736, AF057737, AF057738, AF057739 Genomic DNA. Translation: AAD08652.1.
BC003098 mRNA. Translation: AAH03098.1.

IPI

IPI00019912.

PIR

S59136.

RefSeq

NP_000405.1.

UniGene

Hs.406861

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1IKT	X-ray	1.75	A	618-736	[»]
1S9C	X-ray	3.00	A/B/C/D/E/F/G/H/I/J/K/L	320-614	[»]
1ZBQ	X-ray	2.71	A/B/C/D/E/F	1-304	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

P51659. 3 interactions.

STRING

P51659.

PTM databases

PhosphoSite

P51659.

Proteomic databases

PeptideAtlas

P51659.

PRIDE

P51659.

Genome annotation databases

Ensembl

ENST00000256216; ENSP00000256216; ENSG00000133835; Homo sapiens. [Genome view]
ENST00000414835; ENSP00000411960; ENSG00000133835; Homo sapiens. [Genome view]
ENST00000442060; ENSP00000390208; ENSG00000133835; Homo sapiens. [Genome view]

GeneID

3295.

KEGG

hsa:3295.

UCSC

uc003ksj.2. human.

Organism-specific databases

CTD

3295.

GeneCards

GC05P118816.

H-InvDB

HIX0005116.

HGNC

HGNC:5213. HSD17B4.

HPA

HPA021302.
HPA021311.
HPA021479.

MIM

261515. phenotype.
601860. gene.

Orphanet

300. Bifunctional enzyme deficiency.
2981. Pseudo-Zellweger syndrome.
912. Zellweger syndrome.

PharmGKB

PA29481.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P51659.

HOVERGEN

P51659.

OMA

NQPMTPE.

Enzyme and pathway databases

BRENDA

1.1.1.35. 247.
4.2.1.107. 247.

Reactome

REACT_602. Metabolism of lipids and lipoproteins.

Gene expression databases

ArrayExpress

P51659.

Bgee

P51659.

CleanEx

HS_HSD17B4.

Genevestigator

P51659.

GermOnline

ENSG00000133835. Homo sapiens.

Family and domain databases

InterPro

IPR002198. DH_sc/Rdtase_SDR.
IPR002347. Glc/ribitol_DH.
IPR002539. MaoC_deHydtase.
IPR016040. NAD(P)-bd_dom.
IPR003033. SCP2_sterol_bd.
[Graphical view]

Gene3D

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

PANTHER

PTHR19410. ADH_short_C2. 1 hit.

Pfam

PF00106. adh_short. 1 hit.
PF01575. MaoC_dehydratas. 1 hit.
PF02036. SCP2. 1 hit.
[Graphical view]

PRINTS

PR00081. GDHRDH.
PR00080. SDRFAMILY.

PROSITE

PS00061. ADH_SHORT. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

DB00157. NADH.

NextBio

13071.

SOURCE

Search...

Entry information

Entry name

DHB4_HUMAN

Accession

Primary (citable) accession number: P51659

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	January 23, 2007
Last modified:	November 3, 2009
This is version 103 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.