ID   ACADM_DROME             Reviewed;         419 AA.
AC   Q9VSA3;
DT   12-FEB-2003, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-2000, sequence version 1.
DT   27-MAR-2024, entry version 171.
DE   RecName: Full=Medium-chain specific acyl-CoA dehydrogenase, mitochondrial {ECO:0000303|PubMed:29563254};
DE            EC=1.3.8.7 {ECO:0000269|PubMed:29563254};
DE   Flags: Precursor;
GN   Name=Mcad {ECO:0000303|PubMed:29563254,
GN   ECO:0000312|FlyBase:FBgn0035811};
GN   ORFNames=CG12262 {ECO:0000312|FlyBase:FBgn0035811};
OS   Drosophila melanogaster (Fruit fly).
OC   Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota;
OC   Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea;
OC   Drosophilidae; Drosophila; Sophophora.
OX   NCBI_TaxID=7227;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=Berkeley;
RX   PubMed=10731132; DOI=10.1126/science.287.5461.2185;
RA   Adams M.D., Celniker S.E., Holt R.A., Evans C.A., Gocayne J.D.,
RA   Amanatides P.G., Scherer S.E., Li P.W., Hoskins R.A., Galle R.F.,
RA   George R.A., Lewis S.E., Richards S., Ashburner M., Henderson S.N.,
RA   Sutton G.G., Wortman J.R., Yandell M.D., Zhang Q., Chen L.X., Brandon R.C.,
RA   Rogers Y.-H.C., Blazej R.G., Champe M., Pfeiffer B.D., Wan K.H., Doyle C.,
RA   Baxter E.G., Helt G., Nelson C.R., Miklos G.L.G., Abril J.F., Agbayani A.,
RA   An H.-J., Andrews-Pfannkoch C., Baldwin D., Ballew R.M., Basu A.,
RA   Baxendale J., Bayraktaroglu L., Beasley E.M., Beeson K.Y., Benos P.V.,
RA   Berman B.P., Bhandari D., Bolshakov S., Borkova D., Botchan M.R., Bouck J.,
RA   Brokstein P., Brottier P., Burtis K.C., Busam D.A., Butler H., Cadieu E.,
RA   Center A., Chandra I., Cherry J.M., Cawley S., Dahlke C., Davenport L.B.,
RA   Davies P., de Pablos B., Delcher A., Deng Z., Mays A.D., Dew I.,
RA   Dietz S.M., Dodson K., Doup L.E., Downes M., Dugan-Rocha S., Dunkov B.C.,
RA   Dunn P., Durbin K.J., Evangelista C.C., Ferraz C., Ferriera S.,
RA   Fleischmann W., Fosler C., Gabrielian A.E., Garg N.S., Gelbart W.M.,
RA   Glasser K., Glodek A., Gong F., Gorrell J.H., Gu Z., Guan P., Harris M.,
RA   Harris N.L., Harvey D.A., Heiman T.J., Hernandez J.R., Houck J., Hostin D.,
RA   Houston K.A., Howland T.J., Wei M.-H., Ibegwam C., Jalali M., Kalush F.,
RA   Karpen G.H., Ke Z., Kennison J.A., Ketchum K.A., Kimmel B.E., Kodira C.D.,
RA   Kraft C.L., Kravitz S., Kulp D., Lai Z., Lasko P., Lei Y., Levitsky A.A.,
RA   Li J.H., Li Z., Liang Y., Lin X., Liu X., Mattei B., McIntosh T.C.,
RA   McLeod M.P., McPherson D., Merkulov G., Milshina N.V., Mobarry C.,
RA   Morris J., Moshrefi A., Mount S.M., Moy M., Murphy B., Murphy L.,
RA   Muzny D.M., Nelson D.L., Nelson D.R., Nelson K.A., Nixon K., Nusskern D.R.,
RA   Pacleb J.M., Palazzolo M., Pittman G.S., Pan S., Pollard J., Puri V.,
RA   Reese M.G., Reinert K., Remington K., Saunders R.D.C., Scheeler F.,
RA   Shen H., Shue B.C., Siden-Kiamos I., Simpson M., Skupski M.P., Smith T.J.,
RA   Spier E., Spradling A.C., Stapleton M., Strong R., Sun E., Svirskas R.,
RA   Tector C., Turner R., Venter E., Wang A.H., Wang X., Wang Z.-Y.,
RA   Wassarman D.A., Weinstock G.M., Weissenbach J., Williams S.M., Woodage T.,
RA   Worley K.C., Wu D., Yang S., Yao Q.A., Ye J., Yeh R.-F., Zaveri J.S.,
RA   Zhan M., Zhang G., Zhao Q., Zheng L., Zheng X.H., Zhong F.N., Zhong W.,
RA   Zhou X., Zhu S.C., Zhu X., Smith H.O., Gibbs R.A., Myers E.W., Rubin G.M.,
RA   Venter J.C.;
RT   "The genome sequence of Drosophila melanogaster.";
RL   Science 287:2185-2195(2000).
RN   [2]
RP   GENOME REANNOTATION.
RC   STRAIN=Berkeley;
RX   PubMed=12537572; DOI=10.1186/gb-2002-3-12-research0083;
RA   Misra S., Crosby M.A., Mungall C.J., Matthews B.B., Campbell K.S.,
RA   Hradecky P., Huang Y., Kaminker J.S., Millburn G.H., Prochnik S.E.,
RA   Smith C.D., Tupy J.L., Whitfield E.J., Bayraktaroglu L., Berman B.P.,
RA   Bettencourt B.R., Celniker S.E., de Grey A.D.N.J., Drysdale R.A.,
RA   Harris N.L., Richter J., Russo S., Schroeder A.J., Shu S.Q., Stapleton M.,
RA   Yamada C., Ashburner M., Gelbart W.M., Rubin G.M., Lewis S.E.;
RT   "Annotation of the Drosophila melanogaster euchromatic genome: a systematic
RT   review.";
RL   Genome Biol. 3:RESEARCH0083.1-RESEARCH0083.22(2002).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=Berkeley; TISSUE=Embryo;
RX   PubMed=12537569; DOI=10.1186/gb-2002-3-12-research0080;
RA   Stapleton M., Carlson J.W., Brokstein P., Yu C., Champe M., George R.A.,
RA   Guarin H., Kronmiller B., Pacleb J.M., Park S., Wan K.H., Rubin G.M.,
RA   Celniker S.E.;
RT   "A Drosophila full-length cDNA resource.";
RL   Genome Biol. 3:RESEARCH0080.1-RESEARCH0080.8(2002).
RN   [4]
RP   FUNCTION, CATALYTIC ACTIVITY, PATHWAY, SUBCELLULAR LOCATION, DISRUPTION
RP   PHENOTYPE, PHOSPHORYLATION AT SER-347, AND MUTAGENESIS OF SER-347.
RX   PubMed=29563254; DOI=10.1091/mbc.e18-03-0155;
RA   Course M.M., Scott A.I., Schoor C., Hsieh C.H., Papakyrikos A.M.,
RA   Winter D., Cowan T.M., Wang X.;
RT   "Phosphorylation of MCAD selectively rescues PINK1 deficiencies in behavior
RT   and metabolism.";
RL   Mol. Biol. Cell 29:1219-1227(2018).
CC   -!- FUNCTION: Medium-chain specific acyl-CoA dehydrogenase that catalyzes
CC       the first step of mitochondrial fatty acid beta-oxidation, an aerobic
CC       process that breaks down fatty acids into acetyl-CoA and allows the
CC       production of energy from fats (PubMed:29563254). The first step of
CC       fatty acid beta-oxidation consists in the removal of one hydrogen from
CC       C-2 and C-3 of the straight-chain fatty acyl-CoA thioester, resulting
CC       in the formation of trans-2-enoyl-CoA (By similarity). Electron
CC       transfer flavoprotein (ETF) is the electron acceptor that transfers
CC       electrons to the main mitochondrial respiratory chain via ETF-
CC       ubiquinone oxidoreductase (ETF dehydrogenase) (By similarity). May
CC       contribute to Pink1-mediated regulation of fatty acid and amino acid
CC       metabolism, through a mechanism that is independent of its acyl-CoA
CC       dehydrogenase activity (PubMed:29563254).
CC       {ECO:0000250|UniProtKB:P11310, ECO:0000269|PubMed:29563254}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a medium-chain 2,3-saturated fatty acyl-CoA + H(+) + oxidized
CC         [electron-transfer flavoprotein] = a medium-chain (2E)-enoyl-CoA +
CC         reduced [electron-transfer flavoprotein]; Xref=Rhea:RHEA:14477,
CC         Rhea:RHEA-COMP:10685, Rhea:RHEA-COMP:10686, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:57692, ChEBI:CHEBI:58307, ChEBI:CHEBI:83723,
CC         ChEBI:CHEBI:83726; EC=1.3.8.7;
CC         Evidence={ECO:0000269|PubMed:29563254};
CC   -!- COFACTOR:
CC       Name=FAD; Xref=ChEBI:CHEBI:57692;
CC         Evidence={ECO:0000250|UniProtKB:P11310};
CC   -!- PATHWAY: Lipid metabolism; mitochondrial fatty acid beta-oxidation.
CC       {ECO:0000269|PubMed:29563254}.
CC   -!- SUBUNIT: Homotetramer. {ECO:0000250|UniProtKB:P11310}.
CC   -!- SUBCELLULAR LOCATION: Mitochondrion matrix
CC       {ECO:0000269|PubMed:29563254}. Cytoplasm, cytosol
CC       {ECO:0000269|PubMed:29563254}.
CC   -!- PTM: Phosphorylated (PubMed:29563254). Phosphorylation at Ser-347 by
CC       Pink1, may contribute to regulating levels of acylcarnitines and amino
CC       acids such as C3 acylcarnitine, beta alanine, arginine, lysine, and
CC       argininosuccininc acid, but does not appear to be required for function
CC       as a acyl-CoA dehydrogenase (PubMed:29563254).
CC       {ECO:0000269|PubMed:29563254}.
CC   -!- DISRUPTION PHENOTYPE: Defects in fatty acid oxidation results in a
CC       significant increase in the medium-chain acylcarnitines C6, C8, and
CC       C10, which is further elevated under starvation conditions.
CC       {ECO:0000269|PubMed:29563254}.
CC   -!- SIMILARITY: Belongs to the acyl-CoA dehydrogenase family.
CC       {ECO:0000305}.
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DR   EMBL; AE014296; AAF50524.1; -; Genomic_DNA.
DR   EMBL; AY089546; AAL90284.1; -; mRNA.
DR   RefSeq; NP_648149.1; NM_139892.3.
DR   AlphaFoldDB; Q9VSA3; -.
DR   SMR; Q9VSA3; -.
DR   BioGRID; 64295; 94.
DR   DIP; DIP-20518N; -.
DR   IntAct; Q9VSA3; 7.
DR   STRING; 7227.FBpp0076520; -.
DR   iPTMnet; Q9VSA3; -.
DR   PaxDb; 7227-FBpp0076520; -.
DR   DNASU; 38864; -.
DR   EnsemblMetazoa; FBtr0076808; FBpp0076520; FBgn0035811.
DR   GeneID; 38864; -.
DR   KEGG; dme:Dmel_CG12262; -.
DR   UCSC; CG12262-RA; d. melanogaster.
DR   AGR; FB:FBgn0035811; -.
DR   CTD; 38864; -.
DR   FlyBase; FBgn0035811; Mcad.
DR   VEuPathDB; VectorBase:FBgn0035811; -.
DR   eggNOG; KOG0140; Eukaryota.
DR   GeneTree; ENSGT00940000165774; -.
DR   HOGENOM; CLU_018204_0_2_1; -.
DR   InParanoid; Q9VSA3; -.
DR   OMA; KCHAADV; -.
DR   OrthoDB; 275353at2759; -.
DR   PhylomeDB; Q9VSA3; -.
DR   Reactome; R-DME-77288; mitochondrial fatty acid beta-oxidation of unsaturated fatty acids.
DR   Reactome; R-DME-77346; Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA.
DR   Reactome; R-DME-77348; Beta oxidation of octanoyl-CoA to hexanoyl-CoA.
DR   UniPathway; UPA00660; -.
DR   BioGRID-ORCS; 38864; 0 hits in 3 CRISPR screens.
DR   GenomeRNAi; 38864; -.
DR   PRO; PR:Q9VSA3; -.
DR   Proteomes; UP000000803; Chromosome 3L.
DR   Bgee; FBgn0035811; Expressed in secondary oocyte and 46 other cell types or tissues.
DR   ExpressionAtlas; Q9VSA3; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR   GO; GO:0005759; C:mitochondrial matrix; IEA:UniProtKB-SubCell.
DR   GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR   GO; GO:0003995; F:acyl-CoA dehydrogenase activity; ISS:UniProtKB.
DR   GO; GO:0050660; F:flavin adenine dinucleotide binding; IEA:InterPro.
DR   GO; GO:0070991; F:medium-chain-acyl-CoA dehydrogenase activity; IMP:UniProtKB.
DR   GO; GO:0006635; P:fatty acid beta-oxidation; ISS:UniProtKB.
DR   GO; GO:0051793; P:medium-chain fatty acid catabolic process; IBA:GO_Central.
DR   CDD; cd01157; MCAD; 1.
DR   Gene3D; 1.10.540.10; Acyl-CoA dehydrogenase/oxidase, N-terminal domain; 1.
DR   Gene3D; 2.40.110.10; Butyryl-CoA Dehydrogenase, subunit A, domain 2; 1.
DR   Gene3D; 1.20.140.10; Butyryl-CoA Dehydrogenase, subunit A, domain 3; 1.
DR   InterPro; IPR006089; Acyl-CoA_DH_CS.
DR   InterPro; IPR006091; Acyl-CoA_Oxase/DH_mid-dom.
DR   InterPro; IPR046373; Acyl-CoA_Oxase/DH_mid-dom_sf.
DR   InterPro; IPR036250; AcylCo_DH-like_C.
DR   InterPro; IPR009075; AcylCo_DH/oxidase_C.
DR   InterPro; IPR013786; AcylCoA_DH/ox_N.
DR   InterPro; IPR037069; AcylCoA_DH/ox_N_sf.
DR   InterPro; IPR009100; AcylCoA_DH/oxidase_NM_dom_sf.
DR   InterPro; IPR034180; MCAD.
DR   PANTHER; PTHR48083:SF2; MEDIUM-CHAIN SPECIFIC ACYL-COA DEHYDROGENASE, MITOCHONDRIAL; 1.
DR   PANTHER; PTHR48083; MEDIUM-CHAIN SPECIFIC ACYL-COA DEHYDROGENASE, MITOCHONDRIAL-RELATED; 1.
DR   Pfam; PF00441; Acyl-CoA_dh_1; 1.
DR   Pfam; PF02770; Acyl-CoA_dh_M; 1.
DR   Pfam; PF02771; Acyl-CoA_dh_N; 1.
DR   SUPFAM; SSF47203; Acyl-CoA dehydrogenase C-terminal domain-like; 1.
DR   SUPFAM; SSF56645; Acyl-CoA dehydrogenase NM domain-like; 1.
DR   PROSITE; PS00072; ACYL_COA_DH_1; 1.
DR   PROSITE; PS00073; ACYL_COA_DH_2; 1.
DR   Genevisible; Q9VSA3; DM.
PE   1: Evidence at protein level;
KW   Cytoplasm; FAD; Fatty acid metabolism; Flavoprotein; Lipid metabolism;
KW   Mitochondrion; Oxidoreductase; Phosphoprotein; Reference proteome;
KW   Transit peptide.
FT   TRANSIT         1..22
FT                   /note="Mitochondrion"
FT                   /evidence="ECO:0000255"
FT   CHAIN           23..419
FT                   /note="Medium-chain specific acyl-CoA dehydrogenase,
FT                   mitochondrial"
FT                   /evidence="ECO:0000255"
FT                   /id="PRO_0000000508"
FT   ACT_SITE        397
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000250|UniProtKB:P41367"
FT   BINDING         154..163
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /ligand_note="ligand shared between dimeric partners"
FT                   /note="in other chain"
FT                   /evidence="ECO:0000250|UniProtKB:P41367"
FT   BINDING         163
FT                   /ligand="octanoyl-CoA"
FT                   /ligand_id="ChEBI:CHEBI:57386"
FT                   /evidence="ECO:0000250|UniProtKB:P41367"
FT   BINDING         187..189
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /ligand_note="ligand shared between dimeric partners"
FT                   /note="in other chain"
FT                   /evidence="ECO:0000250|UniProtKB:P41367"
FT   BINDING         212
FT                   /ligand="octanoyl-CoA"
FT                   /ligand_id="ChEBI:CHEBI:57386"
FT                   /evidence="ECO:0000250|UniProtKB:P41367"
FT   BINDING         274
FT                   /ligand="octanoyl-CoA"
FT                   /ligand_id="ChEBI:CHEBI:57386"
FT                   /evidence="ECO:0000250|UniProtKB:P41367"
FT   BINDING         277
FT                   /ligand="octanoyl-CoA"
FT                   /ligand_id="ChEBI:CHEBI:57386"
FT                   /evidence="ECO:0000250|UniProtKB:P41367"
FT   BINDING         302..304
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /ligand_note="ligand shared between dimeric partners"
FT                   /evidence="ECO:0000250|UniProtKB:P41367"
FT   BINDING         312..313
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /ligand_note="ligand shared between dimeric partners"
FT                   /note="in other chain"
FT                   /evidence="ECO:0000250|UniProtKB:P41367"
FT   BINDING         345
FT                   /ligand="octanoyl-CoA"
FT                   /ligand_id="ChEBI:CHEBI:57386"
FT                   /evidence="ECO:0000250|UniProtKB:P41367"
FT   BINDING         347
FT                   /ligand="octanoyl-CoA"
FT                   /ligand_id="ChEBI:CHEBI:57386"
FT                   /evidence="ECO:0000250|UniProtKB:P41367"
FT   BINDING         370..374
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /ligand_note="ligand shared between dimeric partners"
FT                   /evidence="ECO:0000250|UniProtKB:P41367"
FT   BINDING         397
FT                   /ligand="octanoyl-CoA"
FT                   /ligand_id="ChEBI:CHEBI:57386"
FT                   /evidence="ECO:0000250|UniProtKB:P41367"
FT   BINDING         398..401
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /ligand_note="ligand shared between dimeric partners"
FT                   /note="in other chain"
FT                   /evidence="ECO:0000250|UniProtKB:P41367"
FT   MOD_RES         347
FT                   /note="Phosphoserine; by Pink1"
FT                   /evidence="ECO:0000269|PubMed:29563254"
FT   MUTAGEN         347
FT                   /note="S->A: Prevents phosphorylation by Pink1. Does not
FT                   rescue climbing and flight defects in Pink1 mutants."
FT                   /evidence="ECO:0000269|PubMed:29563254"
FT   MUTAGEN         347
FT                   /note="S->D: Phosphomimetic mutant that fully rescues
FT                   climbing defects and significantly improves flight defects,
FT                   and thorax and wing posture phenotypes in Pink1 mutants. No
FT                   effect on acyl-CoA dehydrogenase activity."
FT                   /evidence="ECO:0000269|PubMed:29563254"
FT   MUTAGEN         347
FT                   /note="S->DD: Phosphomimetic mutant that fully rescues
FT                   climbing defects and significantly improves flight defects,
FT                   and thorax and wing posture phenotypes in Pink1 mutants. No
FT                   effect on acyl-CoA dehydrogenase activity."
FT                   /evidence="ECO:0000269|PubMed:29563254"
SQ   SEQUENCE   419 AA;  45871 MW;  0B1970302243C394 CRC64;
     MAFLNKLAAP ALRQLVSQSR AYAAVSHVSP NGTSFALTED QLQLQELARK FTREEIIPVA
     AQYDKSGEYP WPIIKKAWEL GLMNNHIPAD IGGLDLDVFT TCLSAEELAY GCTGIMTALE
     ASGLGQTPVI LSGNKEQKKK YLGRLLEEPL VAAYCVTEPG AGSDVSGIKT RAEKKGDEWV
     INGQKMWITN GGVANWYFVL ARTNPDPKCP PSKAFTGFIV ERDSPGLTPG RKELNMGQRA
     SDTRGITFED VRVPKENVLI GEGAGFKIAM GTFDKTRPPV AAGAVGLAQR CLDEALKYAL
     ERKTFGVPIA YHQAVQFMLA DMAIGVETSR LAWRLSAWEI DQGRRNSYYA SIAKCHAADM
     ANKIASDAVQ IFGGNGFNSE YPVEKLMRDA KIYQIYEGTS QIQRLIISRN MYEAAKGQA
//