Medium-chain specific acyl-CoA dehydrogenase, mitochondrial precursor

Names and origin

Protein names

Recommended name:
    Medium-chain specific acyl-CoA dehydrogenase, mitochondrial
      Short name=MCAD
    EC=1.3.99.3

Gene names

Name:

ACADM

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

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Protein attributes

Sequence length	421 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	This enzyme is specific for acyl chain lengths of 4 to 16.
Catalytic activity	Acyl-CoA + acceptor = 2,3-dehydroacyl-CoA + reduced acceptor.
Cofactor	FAD.
Pathway	Lipid metabolism; mitochondrial fatty acid beta-oxidation.
Subunit structure	Homotetramer. Interacts with the heterodimeric electron transfer flavoprotein ETF.
Subcellular location	Mitochondrion matrix.
Involvement in disease	Defects in ACADM are the cause of medium-chain acyl-CoA dehydrogenase deficiency (MCAD deficiency) [MIM:201450]. It is an autosomal recessive disease which causes fasting hypoglycemia, hepatic dysfunction, and encephalopathy, often resulting in death in infancy. The disease frequency is one in 13000.
Miscellaneous	A number of straight-chain acyl-CoA dehydrogenases of different substrate specificities are present in mammalian tissues. Utilizes the electron transfer flavoprotein (ETF) as electron acceptor that transfers the electrons to the main mitochondrial respiratory chain via ETF-ubiquinone oxidoreductase (ETF dehydrogenase).
Sequence similarities	Belongs to the acyl-CoA dehydrogenase family.

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Ontologies

Keywords
Biological process	Fatty acid metabolism Lipid metabolism
Cellular component	Mitochondrion
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Transit peptide
Ligand	FAD Flavoprotein
Molecular function	Oxidoreductase
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	fatty acid beta-oxidation Ref.6 Inferred from mutant phenotype. Source: UniProtKB oxidation reduction Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	mitochondrial matrix Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	FAD binding Inferred from electronic annotation. Source: InterPro acyl-CoA dehydrogenase activity Ref.6 Inferred from mutant phenotype. Source: UniProtKB electron carrier activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – 25

25

Mitochondrion

Chain

26 – 421

396

Medium-chain specific acyl-CoA dehydrogenase, mitochondrial

PRO_0000000502

Regions

Nucleotide binding

158 – 167

10

FAD

Nucleotide binding

191 – 193

3

FAD

Nucleotide binding

306 – 308

3

FAD

Nucleotide binding

316 – 317

2

FAD

Nucleotide binding

374 – 378

5

FAD

Nucleotide binding

403 – 405

3

FAD

Region

278 – 281

4

Substrate binding

Sites

Active site

401

1

Proton acceptor

Binding site

167

1

Substrate; via carbonyl oxygen

Binding site

402

1

Substrate; via amide nitrogen

Natural variations

Natural variant

53

1

R → C in MCAD deficiency.

VAR_000317

Natural variant

67

1

Y → H in MCAD deficiency; mild.

VAR_013698

Natural variant

78

1

I → T in MCAD deficiency.

VAR_015954

Natural variant

115 – 116

2

Missing in MCAD deficiency.

VAR_000318

Natural variant

116

1

C → Y in MCAD deficiency.

VAR_015955

Natural variant

121

1

T → I in MCAD deficiency.

VAR_015956

Natural variant

132

1

P → R in a breast cancer sample; somatic mutation.

VAR_035716

Natural variant

149

1

M → I in MCAD deficiency.

VAR_000319

Natural variant

193

1

T → A in MCAD deficiency; the thermostability is markedly decreased.

VAR_000320

Natural variant

195

1

G → R in MCAD deficiency.

VAR_000321

Natural variant

206

1

R → L in MCAD deficiency.

VAR_015957

Natural variant

244

1

C → R in MCAD deficiency.

VAR_000322

Natural variant

245

1

S → L in MCAD deficiency.

VAR_013699

Natural variant

267

1

G → R in MCAD deficiency.

VAR_000323

Natural variant

281

1

R → T in MCAD deficiency; mild or benign clinical phenotype.

VAR_013700

Natural variant

310

1

G → R in MCAD deficiency.

VAR_015958

Natural variant

326

1

M → T in MCAD deficiency.

VAR_000324

Natural variant

329

1

K → E in MCAD deficiency; most common variant.

VAR_000325

Natural variant

336

1

S → R in MCAD deficiency.

VAR_000326

Natural variant

352

1

Y → C in MCAD deficiency.

VAR_015959

Natural variant

375

1

I → T in MCAD deficiency.

VAR_000327

Experimental info

Mutagenesis

86

1

L → M: Strongly reduced rate of electron transfer to ETF

Mutagenesis

98

1

L → W: Strongly reduced rate of electron transfer to ETF

Mutagenesis

100

1

L → Y: Strongly reduced rate of electron transfer to ETF

Mutagenesis

108

1

I → M: Strongly reduced rate of electron transfer to ETF

Mutagenesis

191

1

W → A: Loss of electron transfer to ETF

Mutagenesis

191

1

W → F: Reduces rate of electron transfer to ETF about six-fold

Mutagenesis

237

1

E → A: Strongly reduced rate of electron transfer to ETF

Mutagenesis

384

1

E → A: Reduces rate of electron transfer to ETF three-fold

Mutagenesis

384

1

E → Q: Reduces rate of electron transfer to ETF two-fold

Sequence conflict

10

1

R → RCSLQ in AAF63626. Ref.3

Sequence conflict

356

1

I → T in AAF63626. Ref.3

Secondary structure

1

.

421

Helix Strand Turn

Details...

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Sequences

Sequence

Length

Mass (Da)

Tools

P11310-1 [UniParc].

Last modified July 1, 1989. Version 1.
Checksum: 7CD0B5832410581B
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FASTA

421

46,588

        10         20         30         40         50         60 
MAAGFGRCCR VLRSISRFHW RSQHTKANRQ REPGLGFSFE FTEQQKEFQA TARKFAREEI 

        70         80         90        100        110        120 
IPVAAEYDKT GEYPVPLIRR AWELGLMNTH IPENCGGLGL GTFDACLISE ELAYGCTGVQ 

       130        140        150        160        170        180 
TAIEGNSLGQ MPIIIAGNDQ QKKKYLGRMT EEPLMCAYCV TEPGAGSDVA GIKTKAEKKG 

       190        200        210        220        230        240 
DEYIINGQKM WITNGGKANW YFLLARSDPD PKAPANKAFT GFIVEADTPG IQIGRKELNM 

       250        260        270        280        290        300 
GQRCSDTRGI VFEDVKVPKE NVLIGDGAGF KVAMGAFDKT RPVVAAGAVG LAQRALDEAT 

       310        320        330        340        350        360 
KYALERKTFG KLLVEHQAIS FMLAEMAMKV ELARMSYQRA AWEVDSGRRN TYYASIAKAF 

       370        380        390        400        410        420 
AGDIANQLAT DAVQILGGNG FNTEYPVEKL MRDAKIYQIY EGTSQIQRLI VAREHIDKYK 


N

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References

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[1]	"Nucleotide sequence of medium-chain acyl-CoA dehydrogenase mRNA and its expression in enzyme-deficient human tissue." Kelly D.P., Kim J.-J.P., Billadello J.J., Hainline B.E., Chu T.W., Strauss A.W. Proc. Natl. Acad. Sci. U.S.A. 84:4068-4072(1987) [PubMed: 3035565] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Structural organization and regulatory regions of the human medium-chain acyl-CoA dehydrogenase gene." Zhang Z.F., Kelly D.P., Kim J.-J.P., Zhou Y.Q., Ogden M.L., Whelan A.J., Strauss A.W. Biochemistry 31:81-89(1992) [PubMed: 1731887] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Medium-chain acyl-CoA dehydrogenase." Sun F., Wang Y., Block G.D. Submitted (MAR-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Colon.
[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: Liver.
[5]	Lubec G., Vishwanath V. Submitted (MAR-2007) to UniProtKB Cited for: PROTEIN SEQUENCE OF 218-235, MASS SPECTROMETRY. Tissue: Brain and Cajal-Retzius cell.
[6]	"Identification of a common mutation in patients with medium-chain acyl-CoA dehydrogenase deficiency." Matsubara Y., Narisawa K., Miyabayashi S., Tada K., Coates P.M., Bachmann C., Elsas L.J. II, Pollitt R.J., Rhead W.J., Roe C.R. Biochem. Biophys. Res. Commun. 171:498-505(1990) [PubMed: 2393404] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 314-342, VARIANT MCAD DEFICIENCY GLU-329.
[7]	"Crystal structures of the wild type and the Glu376Gly/Thr255Glu mutant of human medium-chain acyl-CoA dehydrogenase: influence of the location of the catalytic base on substrate specificity." Lee H.J., Wang M., Paschke R., Nandy A., Ghisla S., Kim J.-J.P. Biochemistry 35:12412-12420(1996) [PubMed: 8823176] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) IN COMPLEX WITH FAD AND OCTANOYL-COENZYME A, SUBUNIT.
[8]	"Extensive domain motion and electron transfer in the human electron transferring flavoprotein-medium chain acyl-CoA dehydrogenase complex." Toogood H.S., van Thiel A., Basran J., Sutcliffe M.J., Scrutton N.S., Leys D. J. Biol. Chem. 279:32904-32912(2004) [PubMed: 15159392] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 26-421 IN COMPLEXES WITH FAD AND THE ETFA-ETFB HETERODIMER, MUTAGENESIS OF LEU-86; LEU-98; LEU-100; ILE-108; GLU-237 AND GLU-384, SUBUNIT.
[9]	"Stabilization of non-productive conformations underpins rapid electron transfer to electron-transferring flavoprotein." To

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Keywords

Gene Ontology (GO)

Sequence annotation (Features)

Molecule processing

Regions

Sites

Natural variations

Experimental info

Secondary structure

Sequences

References