Q9UKU7 (ACAD8_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Isobutyryl-CoA dehydrogenase, mitochondrial
EC=1.3.99.-

Alternative name(s):
Activator-recruited cofactor 42 kDa component
Short name=ARC42
Acyl-CoA dehydrogenase family member 8
Short name=ACAD-8

Gene names

Name:	ACAD8
Synonyms:	ARC42, IBD

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	415 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	Has very high activity toward isobutyryl-CoA. Is an isobutyryl-CoA dehydrogenase that functions in valine catabolism. Plays a role in transcriptional coactivation within the ARC complex. Ref.2 Ref.7
Catalytic activity	Isobutyryl-CoA + ETF = methylacrylyl-CoA + reduced ETF.
Cofactor	FAD.
Pathway	Amino-acid degradation; L-valine degradation.
Subunit structure	Homotetramer, formed by a dimer of dimers. Subunit of the large multiprotein complex ARC/DRIP. Ref.2 Ref.6
Subcellular location	Mitochondrion Ref.2.
Tissue specificity	Detected at comparable levels in all tissues examined (heart, lung, brain, skeletal muscle, pancreas and placenta). Weakly expressed in liver and kidney.
Involvement in disease	Defects in ACAD8 are the cause of isobutyryl-CoA dehydrogenase deficiency (IBDD) [MIM:611283]. The symptoms of IBDD generally appear until late in infancy or in childhood and can include poor feeding and growth (failure to thrive), a weakened and enlarged heart (dilated cardiomyopathy), seizures, and low numbers of red blood cells (anemia). Ref.7 Ref.8 Ref.9
Sequence similarities	Belongs to the acyl-CoA dehydrogenase family.

Ontologies

Keywords
Biological process	Branched-chain amino acid catabolism Transcription Transcription regulation
Cellular component	Mitochondrion
Disease	Disease mutation
Domain	Transit peptide
Ligand	FAD Flavoprotein
Molecular function	Activator Oxidoreductase
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	branched chain family amino acid catabolic process Traceable author statement. Source: Reactome lipid metabolic process Traceable author statement. Source: ProtInc regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	mitochondrial matrix Traceable author statement. Source: Reactome
Molecular function	acyl-CoA dehydrogenase activity Inferred from experiment. Source: Reactome flavin adenine dinucleotide binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – 22

22

Mitochondrion Potential

Chain

23 – 415

393

Isobutyryl-CoA dehydrogenase, mitochondrial

PRO_0000000522

Regions

Nucleotide binding

158 – 167

10

FAD

Nucleotide binding

191 – 193

3

FAD

Nucleotide binding

312 – 313

2

FAD; shared with dimeric partner

Nucleotide binding

371 – 375

5

FAD; shared with dimeric partner

Nucleotide binding

400 – 402

3

FAD

Region

274 – 277

4

Substrate binding

Sites

Active site

398

1

Proton acceptor

Binding site

167

1

Substrate; via carbonyl oxygen

Binding site

302

1

FAD; shared with dimeric partner

Binding site

399

1

Substrate; via amide nitrogen

Binding site

410

1

Substrate

Natural variations

Natural variant

128

1

M → I in IBDD. Ref.8

VAR_035071

Natural variant

134

1

D → Y in IBDD. Ref.9

VAR_035072

Natural variant

137

1

G → R in IBDD; complete loss of activity. Ref.9

VAR_035073

Natural variant

152

1

M → T in IBDD. Ref.9

VAR_035074

Natural variant

203

1

V → I in IBDD. Ref.8

VAR_035075

Natural variant

302

1

R → Q in IBDD; complete loss of activity. Ref.7 Ref.9

VAR_035076

Natural variant

320

1

A → T in IBDD; <20% of wild-type activity. Ref.9

VAR_035077

Natural variant

334

1

R → C in IBDD. Ref.9

VAR_035078

Natural variant

385

1

Q → R in IBDD. Ref.9

VAR_035079

Experimental info

Sequence conflict

210

1

P → L in AAH01964. Ref.4

Secondary structure

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415

Helix Strand Turn

Details...

Turn

37 – 40

4

Helix

43 – 59

17

Turn

60 – 63

4

Helix

64 – 70

7

Helix

75 – 83

9

Helix

93 – 95

3

Helix

102 – 113

12

Helix

117 – 136

20

Helix

139 – 150

12

Beta strand

156 – 159

4

Beta strand

165 – 168

4

Helix

169 – 171

3

Beta strand

175 – 179

5

Beta strand

182 – 193

12

Turn

194 – 197

4

Beta strand

199 – 211

13

Helix

212 – 214

3

Beta strand

215 – 221

7

Beta strand

227 – 229

3

Beta strand

235 – 237

3

Beta strand

243 – 254

12

Helix

255 – 257

3

Beta strand

258 – 261

4

Helix

265 – 301

37

Helix

309 – 311

3

Helix

313 – 341

29

Helix

347 – 372

26

Helix

373 – 378

6

Helix

384 – 393

10

Turn

394 – 396

3

Beta strand

397 – 399

3

Helix

401 – 414

14

Sequences

	Sequence		Length	Mass (Da)
	Q9UKU7 [UniParc]. Last modified May 1, 2000. Version 1. Checksum: CAFFE91B74E2362D	FASTA	415	45,070
	10 20 30 40 50 60 MLWSGCRRFG ARLGCLPGGL RVLVQTGHRS LTSCIDPSMG LNEEQKEFQK VAFDFAAREM 70 80 90 100 110 120 APNMAEWDQK ELFPVDVMRK AAQLGFGGVY IQTDVGGSGL SRLDTSVIFE ALATGCTSTT 130 140 150 160 170 180 AYISIHNMCA WMIDSFGNEE QRHKFCPPLC TMEKFASYCL TEPGSGSDAA SLLTSAKKQG 190 200 210 220 230 240 DHYILNGSKA FISGAGESDI YVVMCRTGGP GPKGISCIVV EKGTPGLSFG KKEKKVGWNS 250 260 270 280 290 300 QPTRAVIFED CAVPVANRIG SEGQGFLIAV RGLNGGRINI ASCSLGAAHA SVILTRDHLN 310 320 330 340 350 360 VRKQFGEPLA SNQYLQFTLA DMATRLVAAR LMVRNAAVAL QEERKDAVAL CSMAKLFATD 370 380 390 400 410 ECFAICNQAL QMHGGYGYLK DYAVQQYVRD SRVHQILEGS NEVMRILISR SLLQE

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Isolation and characterisation of a cDNA encoding the precursor for a novel member of the acyl-CoA dehydrogenase gene family." Telford E.A.R., Moynihan L.M., Markham A.F., Lench N.J. Biochim. Biophys. Acta 1446:371-376(1999) [PubMed: 10524212] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain and Skin fibroblast.
[2]	"Isolated 2-methylbutyrylglycinuria caused by short/branched-chain acyl-CoA dehydrogenase deficiency: identification of a new enzyme defect, resolution of its molecular basis, and evidence for distinct acyl-CoA dehydrogenases in isoleucine and valine metabolism." Andresen B.S., Christensen E., Corydon T.J., Bross P., Pilgaard B., Wanders R.J.A., Ruiter J.P.N., Simonsen H., Winter V., Knudsen I., Schroeder L.D., Gregersen N., Skovby F. Am. J. Hum. Genet. 67:1095-1103(2000) [PubMed: 11013134] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], PROBABLE FUNCTION, SUBCELLULAR LOCATION, SUBUNIT.
[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].
[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: Cervix.
[5]	"Composite co-activator ARC mediates chromatin-directed transcriptional activation." Naeaer A.M., Beaurang P.A., Zhou S., Abraham S., Solomon W.B., Tjian R. Nature 398:828-832(1999) [PubMed: 10235267] [Abstract] Cited for: IDENTIFICATION IN ARC COMPLEX, PROTEIN SEQUENCE OF 50-61; 70-80 AND 345-355.
[6]	"Structures of isobutyryl-CoA dehydrogenase and enzyme-product complex: comparison with isovaleryl- and short-chain acyl-CoA dehydrogenases." Battaile K.P., Nguyen T.V., Vockley J., Kim J.-J.P. J. Biol. Chem. 279:16526-16534(2004) [PubMed: 14752098] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.77 ANGSTROMS) OF 24-415 IN COMPLEX WITH FAD AND PRODUCT, SUBUNIT.
[7]	"Identification of isobutyryl-CoA dehydrogenase and its deficiency in humans." Nguyen T.V., Andresen B.S., Corydon T.J., Ghisla S., Abd El-Razik N., Mohsen A.W., Cederbaum S.D., Roe D.S., Roe C.R., Lench N.J., Vockley J. Mol. Genet. Metab. 77:68-79(2002) [PubMed: 12359132] [Abstract] Cited for: VARIANT IBDD GLN-302, FUNCTION.
[8]	"Isobutyryl-CoA dehydrogenase deficiency: isobutyrylglycinuria and ACAD8 gene mutations in two infants." Sass J.O., Sander S., Zschocke J. J. Inherit. Metab. Dis. 27:741-745(2004) [PubMed: 15505379] [Abstract] Cited for: VARIANTS IBDD ILE-128 AND ILE-203.
[9]	"Variations in IBD (ACAD8) in children with elevated C4-carnitine detected by tandem mass spectrometry newborn screening." Pedersen C.B., Bischoff C., Christensen E., Simonsen H., Lund A.M., Young S.P., Koeberl D.D., Millington D.S., Roe C.R., Roe D.S., Wanders R.J.A., Ruiter J.P.N., Keppen L.D., Stein Q., Knudsen I., Gregersen N., Andresen B.S. Pediatr. Res. 60:315-320(2006) [PubMed: 16857760] [Abstract] Cited for: VARIANTS IBDD TYR-134; ARG-137; THR-152; GLN-302; THR-320; CYS-334 AND ARG-385, CHARACTERIZATION OF VARIANTS IBDD ARG-137; GLN-302 AND THR-320.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF126245 mRNA. Translation: AAF12736.1.
AF260689 , AF260679, AF260680, AF260681, AF260682, AF260683, AF260684, AF260685, AF260686, AF260687, AF260688 Genomic DNA. Translation: AAF97922.1.
AK000359 mRNA. Translation: BAA91109.1.
BC001964 mRNA. Translation: AAH01964.1.

IPI

IPI00747159.

RefSeq

NP_055199.1. NM_014384.2.

UniGene

Hs.14791.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1RX0	X-ray	1.77	A/B/C/D	24-415	[»]

ProteinModelPortal

Q9UKU7.

SMR

Q9UKU7. Positions 32-415.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9UKU7. 3 interactions.

STRING

Q9UKU7.

PTM databases

PhosphoSite

Q9UKU7.

Polymorphism databases

DMDM

26006699.

2D gel databases

UCD-2DPAGE

Q9UKU7.

Proteomic databases

PRIDE

Q9UKU7.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000281182; ENSP00000281182; ENSG00000151498.

GeneID

27034.

KEGG

hsa:27034.

UCSC

uc001qhk.1. human.

Organism-specific databases

CTD

27034.

GeneCards

GC11P134123.

H-InvDB

HIX0010299.

HGNC

HGNC:87. ACAD8.

MIM

604773. gene.
611283. phenotype.

neXtProt

NX_Q9UKU7.

Orphanet

79159. Isobutyryl-CoA dehydrogenase deficiency.

GenAtlas

Search...

Phylogenomic databases

GeneTree

ENSGT00590000082821.

HOGENOM

HBG699365.

HOVERGEN

HBG000224.

InParanoid

Q9UKU7.

OMA

VLCSMAK.

PhylomeDB

Q9UKU7.

Enzyme and pathway databases

Reactome

REACT_111217. Metabolism.

Gene expression databases

ArrayExpress

Q9UKU7.

Bgee

Q9UKU7.

CleanEx

HS_ACAD8.

Genevestigator

Q9UKU7.

GermOnline

ENSG00000151498. Homo sapiens.

Family and domain databases

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]

Gene3D

G3DSA:2.40.110.10. Acyl_CoA_DH/ox_M. 1 hit.
G3DSA:1.10.540.10. AcylCoA_DH/ox_N. 1 hit.
G3DSA:1.20.140.10. AcylCoA_DH_1/2_C. 1 hit.

KO

K11538.

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. False negative.
[Graphical view]

ProtoNet

Search...

Other

NextBio

49582.

SOURCE

Search...

Entry information

Entry name

ACAD8_HUMAN

Accession

Primary (citable) accession number: Q9UKU7
Secondary accession number(s): Q9BUS8

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 28, 2002
Last sequence update:	May 1, 2000
Last modified:	January 25, 2012
This is version 113 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.