P26440 (IVD_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Isovaleryl-CoA dehydrogenase, mitochondrial
Short name=IVD
EC=1.3.8.4

Gene names

Name:

IVD

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	423 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)

Catalytic activity	Isovaleryl-CoA + electron-transfer flavoprotein = 3-methylcrotonyl-CoA + reduced electron-transfer flavoprotein.
Cofactor	FAD.
Pathway	Amino-acid degradation; L-leucine degradation; (S)-3-hydroxy-3-methylglutaryl-CoA from 3-isovaleryl-CoA: step 1/3.
Subunit structure	Homotetramer.
Subcellular location	Mitochondrion matrix.
Involvement in disease	Isovaleric acidemia (IVA) [MIM:243500]: Characterized by retarded psychomotor development, a peculiar odor resembling sweaty feet, an aversion to dietary protein, and pernicious vomiting, leading to acidosis and coma. The acute neonatal form leads to massive metabolic acidosis from the first days of life and rapid death. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.14 Ref.15
Sequence similarities	Belongs to the acyl-CoA dehydrogenase family.
Sequence caution	The sequence BAG53799.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Ontologies

Keywords
Cellular component	Mitochondrion
Coding sequence diversity	Alternative splicing
Disease	Disease mutation
Domain	Transit peptide
Ligand	FAD Flavoprotein
Molecular function	Oxidoreductase
PTM	Acetylation
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	cellular nitrogen compound metabolic process Traceable author statement. Source: Reactome leucine catabolic process Inferred from sequence or structural similarity. Source: BHF-UCL
Cellular_component	mitochondrial matrix Inferred from sequence or structural similarity. Source: BHF-UCL
Molecular_function	flavin adenine dinucleotide binding Inferred from electronic annotation. Source: InterPro isovaleryl-CoA dehydrogenase activity Inferred from sequence or structural similarity. Source: BHF-UCL
Complete GO annotation...

Alternative products

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

Isoform 1 (identifier: P26440-1)

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 2 (identifier: P26440-2)

The sequence of this isoform differs from the canonical sequence as follows:
     49-78: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – 29

29

Mitochondrion Ref.8 Ref.9

Chain

30 – 423

394

Isovaleryl-CoA dehydrogenase, mitochondrial

PRO_0000000531

Regions

Nucleotide binding

162 – 171

10

FAD

Nucleotide binding

195 – 197

3

FAD

Nucleotide binding

377 – 381

5

FAD

Nucleotide binding

406 – 408

3

FAD

Region

219 – 220

2

Substrate binding

Region

281 – 284

4

Substrate binding

Region

404 – 405

2

Substrate binding

Sites

Active site

283

1

Proton acceptor Ref.10

Binding site

171

1

Substrate; via carbonyl oxygen

Binding site

274

1

Substrate

Binding site

309

1

FAD

Binding site

320

1

FAD

Amino acid modifications

Modified residue

75

1

N6-acetyllysine Ref.11

Natural variations

Alternative sequence

49 – 78

30

Missing in isoform 2.

VSP_045193

Natural variant

42

1

L → P in IVA. Ref.14

VAR_000423

Natural variant

50

1

R → P in IVA. Ref.15

VAR_015960

Natural variant

69

1

D → N in IVA. Ref.15

VAR_015961

Natural variant

199

1

G → V in IVA. Ref.14

VAR_000424

Natural variant

311

1

A → V in IVA. Ref.15

VAR_015962

Natural variant

357

1

C → R in IVA. Ref.15

VAR_015963

Natural variant

371

1

V → A in IVA. Ref.15

VAR_015964

Natural variant

392

1

R → C in IVA. Ref.15

VAR_015965

Natural variant

411

1

R → L in IVA. Ref.15

VAR_015966

Experimental info

Mutagenesis

283

1

E → D: Residual activity. Ref.10

Mutagenesis

283

1

E → G or Q: Loss of activity. Ref.10

Sequence conflict

10

1

W → C in AAH17202. Ref.6

Secondary structure

1

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423

Helix Strand Turn

Details...

Helix

38 – 40

3

Helix

44 – 60

17

Turn

61 – 64

4

Helix

65 – 71

7

Helix

77 – 87

11

Turn

90 – 93

4

Helix

96 – 98

3

Helix

105 – 118

14

Helix

120 – 130

11

Turn

131 – 133

3

Helix

134 – 140

7

Helix

143 – 154

12

Beta strand

160 – 163

4

Beta strand

169 – 172

4

Helix

173 – 175

3

Beta strand

179 – 182

4

Beta strand

184 – 197

14

Helix

199 – 201

3

Beta strand

203 – 211

9

Helix

218 – 221

4

Beta strand

222 – 228

7

Beta strand

234 – 236

3

Beta strand

242 – 244

3

Beta strand

250 – 261

12

Helix

262 – 264

3

Beta strand

265 – 267

3

Helix

272 – 287

16

Helix

289 – 306

18

Helix

316 – 318

3

Helix

320 – 348

29

Helix

354 – 379

26

Helix

380 – 384

5

Helix

390 – 399

10

Turn

400 – 404

5

Helix

407 – 419

13

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified August 1, 1992. Version 1. Checksum: 121AF14C7F1FA13D	FASTA	423	46,319
	10 20 30 40 50 60 MATATRLLGW RVASWRLRPP LAGFVSQRAH SLLPVDDAIN GLSEEQRQLR QTMAKFLQEH 70 80 90 100 110 120 LAPKAQEIDR SNEFKNLREF WKQLGNLGVL GITAPVQYGG SGLGYLEHVL VMEEISRASG 130 140 150 160 170 180 AVGLSYGAHS NLCINQLVRN GNEAQKEKYL PKLISGEYIG ALAMSEPNAG SDVVSMKLKA 190 200 210 220 230 240 EKKGNHYILN GNKFWITNGP DADVLIVYAK TDLAAVPASR GITAFIVEKG MPGFSTSKKL 250 260 270 280 290 300 DKLGMRGSNT CELIFEDCKI PAANILGHEN KGVYVLMSGL DLERLVLAGG PLGLMQAVLD 310 320 330 340 350 360 HTIPYLHVRE AFGQKIGHFQ LMQGKMADMY TRLMACRQYV YNVAKACDEG HCTAKDCAGV 370 380 390 400 410 420 ILYSAECATQ VALDGIQCFG GNGYINDFPM GRFLRDAKLY EIGAGTSEVR RLVIGRAFNA DFH
	Isoform 2 [UniParc]. Checksum: 6C75C436286F2617	FASTA	393	42,724
	10 20 30 40 50 60 MATATRLLGW RVASWRLRPP LAGFVSQRAH SLLPVDDAIN GLSEEQRQEF WKQLGNLGVL 70 80 90 100 110 120 GITAPVQYGG SGLGYLEHVL VMEEISRASG AVGLSYGAHS NLCINQLVRN GNEAQKEKYL 130 140 150 160 170 180 PKLISGEYIG ALAMSEPNAG SDVVSMKLKA EKKGNHYILN GNKFWITNGP DADVLIVYAK 190 200 210 220 230 240 TDLAAVPASR GITAFIVEKG MPGFSTSKKL DKLGMRGSNT CELIFEDCKI PAANILGHEN 250 260 270 280 290 300 KGVYVLMSGL DLERLVLAGG PLGLMQAVLD HTIPYLHVRE AFGQKIGHFQ LMQGKMADMY 310 320 330 340 350 360 TRLMACRQYV YNVAKACDEG HCTAKDCAGV ILYSAECATQ VALDGIQCFG GNGYINDFPM 370 380 390 GRFLRDAKLY EIGAGTSEVR RLVIGRAFNA DFH

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Nucleotide sequence of messenger RNA encoding human isovaleryl-coenzyme A dehydrogenase and its expression in isovaleric acidemia fibroblasts." Matsubara Y., Ito M., Glassberg R., Satyabhama S., Ikeda Y., Tanaka K. J. Clin. Invest. 85:1058-1064(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"Exon skipping in IVD RNA processing in isovaleric acidemia caused by point mutations in the coding region of the IVD gene." Vockley J., Rogan P.K., Anderson B.D., Willard J., Seelan R.S., Smith D.I., Liu W. Am. J. Hum. Genet. 66:356-367(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). Tissue: Pericardium and Testis.
[4]	"Analysis of the DNA sequence and duplication history of human chromosome 15." Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K., Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N., Abouelleil A. , Arachchi H.M., Baradarani L., Birditt B., Bloom S., Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K., DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J., Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E., Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B., Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R., O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B., Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S., Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C. Nature 440:671-675(2006) [PubMed] [Europe PMC] [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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Brain.
[7]	"Structural organization of the human isovaleryl-CoA dehydrogenase gene." Parimoo B., Tanaka K. Genomics 15:582-590(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 381-423.
[8]	"The variant human isovaleryl-CoA dehydrogenase gene responsible for type II isovaleric acidemia determines an RNA splicing error, leading to the deletion of the entire second coding exon and the production of a truncated precursor protein that interacts poorly with mitochondrial import receptors." Vockley J., Nagao M., Parimoo B., Tanaka K. J. Biol. Chem. 267:2494-2501(1992) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF N-TERMINUS.
[9]	"Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides." Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R., Vandekerckhove J. Nat. Biotechnol. 21:566-569(2003) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 30-47. Tissue: Platelet.
[10]	"Identification of the active site catalytic residue in human isovaleryl-CoA dehydrogenase." Mohsen A.W., Vockley J. Biochemistry 34:10146-10152(1995) [PubMed] [Europe PMC] [Abstract] Cited for: ACTIVE SITE, MUTAGENESIS OF GLU-283.
[11]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-75, MASS SPECTROMETRY.
[12]	"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] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[13]	"Structure of human isovaleryl-CoA dehydrogenase at 2.6-A resolution: structural basis for substrate specificity." Tiffany K.A., Roberts D.L., Wang M., Paschke R., Mohsen A.W., Vockley J., Kim J.-J.P. Biochemistry 36:8455-8464(1997) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 30-423 IN COMPLEX WITH FAD AND SUBSTRATE ANALOG.
[14]	"Molecular characterization of four different classes of mutations in the isovaleryl-CoA dehydrogenase gene responsible for isovaleric acidemia." Vockley J., Parimoo B., Tanaka K. Am. J. Hum. Genet. 49:147-157(1991) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS IVA PRO-42 AND VAL-199.
[15]	"Characterization of molecular defects in isovaleryl-CoA dehydrogenase in patients with isovaleric acidemia." Mohsen A.-W.A., Anderson B.D., Volchenboum S.L., Battaile K.P., Tiffany K.A., Roberts D.L., Kim J.-J.P., Vockley J. Biochemistry 37:10325-10335(1998) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS IVA PRO-50; ASN-69; VAL-311; ARG-357; ALA-371; CYS-392 AND LEU-411.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M34192 mRNA. Translation: AAA52711.1.
AF191218 , AF191214, AF191215, AF191216, AF191217 Genomic DNA. Translation: AAF20182.1.
AK122922 mRNA. Translation: BAG53799.1. Different initiation.
AK315296 mRNA. Translation: BAG37702.1.
AC013356 Genomic DNA. No translation available.
CH471125 Genomic DNA. Translation: EAW92414.1.
BC017202 mRNA. Translation: AAH17202.1.
AF038318 Genomic DNA. Translation: AAB92584.1.

IPI

IPI00645805.
IPI00929108.

PIR

A37033.

RefSeq

NP_001152980.1. NM_001159508.1.
NP_002216.2. NM_002225.3.

UniGene

Hs.513646.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1IVH	X-ray	2.60	A/B/C/D	30-423	[»]

ProteinModelPortal

P26440.

ModBase

Search...

Protein-protein interaction databases

IntAct

P26440. 1 interaction.

STRING

9606.ENSP00000249760.

PTM databases

PhosphoSite

P26440.

Polymorphism databases

DMDM

125051.

2D gel databases

REPRODUCTION-2DPAGE

IPI00645805.

UCD-2DPAGE

P26440.

Proteomic databases

PaxDb

P26440.

PRIDE

P26440.

Protocols and materials databases

DNASU

3712.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000249760; ENSP00000249760; ENSG00000128928.
ENST00000479013; ENSP00000417990; ENSG00000128928.

GeneID

3712.

KEGG

hsa:3712.

UCSC

uc001zlq.2. human.
uc001zls.3. human.

Organism-specific databases

CTD

3712.

GeneCards

GC15P040697.

HGNC

HGNC:6186. IVD.

HPA

HPA041391.
HPA044250.

MIM

243500. phenotype.
607036. gene.

neXtProt

NX_P26440.

Orphanet

33. Isovaleric acidemia.

PharmGKB

PA29984.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG1960.

HOGENOM

HOG000131659.

HOVERGEN

HBG000224.

InParanoid

P26440.

KO

K00253.

PhylomeDB

P26440.

Enzyme and pathway databases

Reactome

REACT_111217. Metabolism.

SABIO-RK

P26440.

UniPathway

UPA00363; UER00860.

Gene expression databases

ArrayExpress

P26440.

Bgee

P26440.

CleanEx

HS_IVD.

Genevestigator

P26440.

GermOnline

ENSG00000128928. Homo sapiens.

Family and domain databases

Gene3D

1.10.540.10. 1 hit.
2.40.110.10. 1 hit.

InterPro

IPR006089. Acyl-CoA_DH_CS.
IPR006092. Acyl-CoA_DH_N.
IPR006090. Acyl-CoA_Oxase/DH_1.
IPR006091. Acyl-CoA_Oxase/DH_cen-dom.
IPR009075. AcylCo_DH/oxidase_C.
IPR013786. AcylCoA_DH/ox_N.
IPR009100. AcylCoA_DH/oxidase.
[Graphical view]

Pfam

PF00441. Acyl-CoA_dh_1. 1 hit.
PF02770. Acyl-CoA_dh_M. 1 hit.
PF02771. Acyl-CoA_dh_N. 1 hit.
[Graphical view]

SUPFAM

SSF56645. AcylCoA_dehyd_NM. 1 hit.
SSF47203. AcylCoADH_C_like. 1 hit.

PROSITE

PS00072. ACYL_COA_DH_1. 1 hit.
PS00073. ACYL_COA_DH_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

IVD. human.

EvolutionaryTrace

P26440.

GenomeRNAi

3712.

NextBio

14547.

SOURCE

Search...

Entry information

Entry name

IVD_HUMAN

Accession

Primary (citable) accession number: P26440
Secondary accession number(s): B2RCV5, B3KVI7, Q96AF6

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1992
Last sequence update:	August 1, 1992
Last modified:	May 29, 2013
This is version 148 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.