HMLL_DROME
ID HMLL_DROME Reviewed; 681 AA.
AC Q9V3U0; Q8SWR5;
DT 15-JAN-2008, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 138.
DE RecName: Full=Long-chain-fatty-acid--CoA ligase heimdall {ECO:0000303|PubMed:25409104, ECO:0000312|FlyBase:FBgn0286723};
DE EC=6.2.1.3 {ECO:0000305|PubMed:26893370};
DE AltName: Full=Very long-chain-fatty-acid--CoA ligase double bubble {ECO:0000303|PubMed:26893370};
GN Name=hll {ECO:0000303|PubMed:25409104, ECO:0000312|FlyBase:FBgn0286723};
GN Synonyms=BG:DS05899.1 {ECO:0000312|FlyBase:FBgn0286723},
GN dbb {ECO:0000312|FlyBase:FBgn0286723};
GN ORFNames=CG4500 {ECO:0000312|FlyBase:FBgn0286723};
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] OF 2-681.
RC STRAIN=Berkeley; TISSUE=Embryo;
RA Stapleton M., Carlson J.W., Chavez C., Frise E., George R.A., Pacleb J.M.,
RA Park S., Wan K.H., Yu C., Rubin G.M., Celniker S.E.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=25409104; DOI=10.5665/sleep.4680;
RA Thimgan M.S., Seugnet L., Turk J., Shaw P.J.;
RT "Identification of genes associated with resilience/vulnerability to sleep
RT deprivation and starvation in Drosophila.";
RL Sleep 38:801-814(2015).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, AND DISRUPTION PHENOTYPE.
RX PubMed=26893370; DOI=10.1242/dmm.022244;
RA Sivachenko A., Gordon H.B., Kimball S.S., Gavin E.J., Bonkowsky J.L.,
RA Letsou A.;
RT "Neurodegeneration in a Drosophila model of adrenoleukodystrophy: the roles
RT of the Bubblegum and Double bubble acyl-CoA synthetases.";
RL Dis. Model. Mech. 9:377-387(2016).
RN [6]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=29739804; DOI=10.1242/dmm.031286;
RA Gordon H.B., Valdez L., Letsou A.;
RT "Etiology and treatment of adrenoleukodystrophy: new insights from
RT Drosophila.";
RL Dis. Model. Mech. 11:0-0(2018).
CC -!- FUNCTION: Mediates activation of long-chain fatty acids for both
CC synthesis of cellular lipids, and degradation via beta-oxidation
CC (PubMed:26893370, PubMed:29739804). Probably by regulating lipid
CC storage and catabolism, plays a role in neuronal function
CC (PubMed:25409104). {ECO:0000269|PubMed:25409104,
CC ECO:0000269|PubMed:26893370, ECO:0000269|PubMed:29739804}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a long-chain fatty acid + ATP + CoA = a long-chain fatty acyl-
CC CoA + AMP + diphosphate; Xref=Rhea:RHEA:15421, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:33019, ChEBI:CHEBI:57287, ChEBI:CHEBI:57560,
CC ChEBI:CHEBI:83139, ChEBI:CHEBI:456215; EC=6.2.1.3;
CC Evidence={ECO:0000305|PubMed:26893370};
CC -!- DISRUPTION PHENOTYPE: Results in neurodegeneration in the central
CC nervous system including degeneration of lamina and retina, defects in
CC the fenestrated basement membrane, ommatidial disarray, locomotor
CC defects and shortened lifespan (PubMed:26893370, PubMed:29739804). The
CC phenotype is exacerbated in constant light conditions and improves in
CC total darkness (PubMed:29739804). Effects are probably due to elevated
CC levels of very long chain fatty acids (VLCFAs) (PubMed:29739804).
CC Feeding the fly mutant with medium-chain fatty acids, blocks the
CC accumulation of excess VLCFAs as well as development of the pathology
CC (PubMed:29739804). Simultaneous knockout of bgm results in enhanced
CC retinal degeneration and altered fatty acids metabolism
CC (PubMed:26893370). RNAi-mediated knockdown in the adult results in
CC reduction of triglycerides and altered neuronal function, including
CC altered sleep rebound following sleep deprivation (PubMed:25409104).
CC {ECO:0000269|PubMed:25409104, ECO:0000269|PubMed:26893370,
CC ECO:0000269|PubMed:29739804}.
CC -!- MISCELLANEOUS: In Norse mythology, Heimdall is the fictional character
CC that for ages guarded the bridge to Asgard without sleeping and without
CC the consequences of sleep deprivation. {ECO:0000305|PubMed:25409104}.
CC -!- SIMILARITY: Belongs to the ATP-dependent AMP-binding enzyme family.
CC Bubblegum subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAM12254.1; Type=Erroneous termination; Note=Truncated C-terminus.; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AE014134; AAF53370.1; -; Genomic_DNA.
DR EMBL; BT021247; AAX33395.1; -; mRNA.
DR EMBL; AY095523; AAM12254.1; ALT_SEQ; mRNA.
DR RefSeq; NP_609696.1; NM_135852.4.
DR AlphaFoldDB; Q9V3U0; -.
DR SMR; Q9V3U0; -.
DR BioGRID; 60849; 1.
DR STRING; 7227.FBpp0080168; -.
DR PaxDb; Q9V3U0; -.
DR PRIDE; Q9V3U0; -.
DR DNASU; 34822; -.
DR EnsemblMetazoa; FBtr0080591; FBpp0080168; FBgn0286723.
DR GeneID; 34822; -.
DR KEGG; dme:Dmel_CG4500; -.
DR UCSC; CG4500-RA; d. melanogaster.
DR CTD; 34822; -.
DR FlyBase; FBgn0286723; hll.
DR VEuPathDB; VectorBase:FBgn0286723; -.
DR eggNOG; KOG1256; Eukaryota.
DR GeneTree; ENSGT00940000172512; -.
DR HOGENOM; CLU_000022_45_5_1; -.
DR InParanoid; Q9V3U0; -.
DR OMA; IGDHRKY; -.
DR OrthoDB; 806831at2759; -.
DR PhylomeDB; Q9V3U0; -.
DR Reactome; R-DME-75876; Synthesis of very long-chain fatty acyl-CoAs.
DR BioGRID-ORCS; 34822; 0 hits in 3 CRISPR screens.
DR GenomeRNAi; 34822; -.
DR PRO; PR:Q9V3U0; -.
DR Proteomes; UP000000803; Chromosome 2L.
DR Bgee; FBgn0286723; Expressed in arthropod fat body and 20 other tissues.
DR Genevisible; Q9V3U0; DM.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0015645; F:fatty acid ligase activity; TAS:FlyBase.
DR GO; GO:0004467; F:long-chain fatty acid-CoA ligase activity; IDA:FlyBase.
DR GO; GO:0006633; P:fatty acid biosynthetic process; TAS:FlyBase.
DR GO; GO:0006631; P:fatty acid metabolic process; IMP:FlyBase.
DR GO; GO:0001676; P:long-chain fatty acid metabolic process; IMP:UniProtKB.
DR GO; GO:0007498; P:mesoderm development; IEP:FlyBase.
DR GO; GO:0070050; P:neuron cellular homeostasis; IMP:FlyBase.
DR GO; GO:0045938; P:positive regulation of circadian sleep/wake cycle, sleep; IMP:FlyBase.
DR GO; GO:0070328; P:triglyceride homeostasis; IMP:FlyBase.
DR Gene3D; 3.40.50.12780; -; 1.
DR InterPro; IPR000873; AMP-dep_Synth/Lig.
DR InterPro; IPR042099; ANL_N_sf.
DR Pfam; PF00501; AMP-binding; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Fatty acid metabolism; Ligase; Lipid metabolism;
KW Nucleotide-binding; Reference proteome.
FT CHAIN 1..681
FT /note="Long-chain-fatty-acid--CoA ligase heimdall"
FT /id="PRO_0000315818"
FT BINDING 223..231
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 414..419
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 491
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 506
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 639
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
SQ SEQUENCE 681 AA; 75152 MW; 6310902CC494712E CRC64;
MNDLKPATSY RSTSLHDAVK LRLDEPSSFS QTVPPQTIPE FFKESCEKYS DLPALVWETP
GSGNDGWTTL TFGEYQERVE QAALMLLSVG VEERSSVGIL AFNCPEWFFA EFGALRAGAV
VAGVYPSNSA EAVHHVLATG ESSVCVVDDA QQMAKLRAIK ERLPRLKAVI QLHGPFEAFV
DHEPGYFSWQ KLQEQTFSSE LKEELLARES RIRANECAML IFTSGTVGMP KAVMLSHDNL
VFDTKSAAAH MQDIQVGKES FVSYLPLSHV AAQIFDVFLG LSHAGCVTFA DKDALKGTLI
KTFRKARPTK MFGVPRVFEK LQERLVAAEA KARPYSRLLL ARARAAVAEH QTTLMAGKSP
SIYGNAKYWL ACRVVKPIRE MIGVDNCRVF FTGGAPTSEE LKQFFLGLDI ALGECYGMSE
TSGAITLNVD ISNLYSAGQA CEGVTLKIHE PDCNGQGEIL MRGRLVFMGY LGLPDKTEET
VKEDGWLHSG DLGYIDPKGN LIISGRLKEL IITAGGENIP PVHIEELIKK ELPCVSNVLL
IGDHRKYLTV LLSLKTKCDA KTGIPLDALR EETIEWLRDL DIHETRLSEL LNIPADLQLP
NDTAALAATL EITAKPKLLE AIEEGIKRAN KYAISNAQKV QKFALIAHEF SVATGELGPT
LKIRRNIVHA KYAKVIERLY K
