By consensus, the acyl-CoA synthetase (ACS) community, with the advice of the human and mouse genome nomenclature committees, has revised the nomenclature for the mammalian long-chain acyl-CoA synthetases. ACS is the family root name, and the human and mouse genes for the long-chain ACSs are terme

Berger, Johannes

Bernlohr, David A.

Black, Paul

Bornfeldt, Karin E.

Coleman, Rosalind A.

DiRusso, Concerta C.

Farber, Steven A.

Guo, Wen

Hashimoto, Naohiro

Khodiyar, Varsha

Kuypers, Frans A.

Maltais, Lois J.

Mashek, Douglas G.

Nebert, Daniel W.

Renieri, Alessandra

Schaffer, Jean E.

Stahl, Andreas

Vasiliou, Vasilis

Watkins, Paul A.

Yamamoto, Tokuo T.

Carolina Digital Repository

 Copyright © 2004 by the American Society for Biochemistry and Molecular Biology, Inc. 1958 Journal of Lipid Research Volume 45, 2004 This article is available online at http://www.jlr.org Revised nomenclature for the mammalian long-chain acyl-CoA synthetase gene family Douglas G. Mashek,* Karin E. Bornfeldt, †  Rosalind A. Coleman, 1, * Johannes Berger, § David A. Bernlohr,** Paul Black, ††  Concetta C. DiRusso, ††  Steven A. Farber, §§  Wen Guo,*** Naohiro Hashimoto, †††  Varsha Khodiyar, §§§  Frans A. Kuypers,**** Lois J. Maltais, †††† Daniel W. Nebert, §§§§  Alessandra Renieri,***** Jean E. Schaffer, †††††  Andreas Stahl, §§§§§ Paul A. Watkins,****** Vasilis Vasiliou, ††††††  and Tokuo T. Yamamoto §§§§§§ Departments of Nutrition and Pediatrics,* University of North Carolina, Chapel Hill, NC 27599; Department of Pathology, †  University of Washington, Seattle, WA 98195; Medical University of Vienna, §  Brain Research Institute, Neuroimmunology, A-1090 Vienna, Austria; Department of Biochemistry, Molecular Biology, and Biophysics,** University of Minnesota, Minneapolis, MN 55455; Ordway Research Institute, Inc., ††  Albany, NY 12208; Department of Microbiology and Immunology, §§  Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107; Department of Medicine,*** Boston University School of Medicine, Boston, MA 01228; Tissue Stem Cell Research Team, †††  Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo194-8511, Japan; The Human Genome Organization Gene Nomenclature Committee, §§§  Department of Biology, University College London, London NW1 2HE, UK; Children’s Hospital Oakland Research Institute,**** Oakland, CA 94609; Mouse Genomic Nomenclature Committee, ††††  The Jackson Laboratory, Bar Harbor, ME 04609; Department of Environmental Health and Center for Environmental Genetics, §§§§  University of Cincinnati Medical Center, Cincinnati OH 45267-0056; Medical Genetics,***** University of Siena, Policlinico Le Scotte, 53100 Siena, Italy; Department of Internal Medicine, †††††  Washington University School of Medicine, St. Louis, MO 63110; Research Institute, §§§§§  Palo Alto Medical Foundation, Palo Alto, CA 94301; Kennedy Krieger Institute,****** Baltimore, MD 21205; Molecular Toxicology and Environmental Health Sciences Program, ††††††  Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, CO 809262; and Center for Advanced Genome Research, §§§§§§  Institute of Development, Aging, and Cancer, Tohoku University, Sendai 981-8555, Japan Abstract By consensus, the acyl-CoA synthetase (ACS) com-munity, with the advice of the human and mouse ge-nome nomenclature committees, has revised the nomencla-ture for the mammalian long-chain acyl-CoA synthetases.ACS is the family root name, and the human and mousegenes for the long-chain ACSs are termed  ACSL1,3–6  and Acsl1,3–6 , respectively. Splice variants of ACSL3, -4, -5, and-6 are cataloged.  Suggestions for naming other familymembers and for the nonmammalian acyl-CoA synthetasesare made. —Mashek, D. G., K. E. Bornfeldt, R. A. Coleman,J. Berger, D. A. Bernlohr, P. Black, C. C. DiRusso, S. A. Far-ber, W. Guo, N. Hashimoto, V. Khodiyar, F. A. Kuypers, L. J.Maltais, D. W. Nebert, A. Renieri, J. E. Schaffer, A. Stahl,P. A. Watkins, V. Vasiliou, and T. T. Yamamoto.  Revised no-menclature for the mammalian long-chain acyl-CoA syn-thetase gene family.  J. Lipid Res.  2004.  45:  1958–1961. Supplementary key words acyl-coenzyme A synthetase  •  fatty acid-coenzyme A ligase  •  coenzyme A synthetase  •  bubblegum  •  fatty acidtransport protein  •  very long chain-acyl-CoA synthetase  •  long-chainacyl-coenzyme A synthetase  •  lipidosin  •  scFat2p In mammals, long-chain acyl-CoA synthetase (ACSL)catalyzes the initial step in cellular long-chain fatty acidmetabolism. In this reaction, ACSL ligates fatty acids toCoA in a two-step reaction (1, 2):  1 ) fatty acid    ATP  → fatty acyl-AMP    pyrophosphate;  2 ) fatty acyl-AMP    CoA →  fatty acyl-CoA    AMP. Since the cDNA encoding ACSLwas cloned in 1990 (3), five isoforms of ACSL differing intheir substrate preferences, enzyme kinetics, cellular andorganelle locations, and regulation have been identifiedand characterized in rodents and humans. Although ourknowledge of the ACSL family has advanced greatly in re-cent years, inconsistencies regarding ACSL nomenclaturehave led to confusion in the scientific literature. To allevi-ate the confusion regarding ACSL naming and number-ing, a group of researchers studying the  ACSL  genes, incoordination with the human and mouse genome nomen-clature committees (HGNC and MGNC), have revised theprevious nomenclature system. The purpose of this reportis to present the revised and approved nomenclature forthe  ACSL  gene family in humans and rodents and to en- 1  To whom correspondence should be addressed.e-mail: rcoleman@unc.edu Manuscript received 25 June 2004 and in revised form 15 July 2004.Published, JLR Papers in Press, August 1, 2004.DOI 10.1194/jlr.E400002-JLR200 reportThis is an open access article under the CC BY license. Mashek et al. Mammalian long-chain acyl-CoA synthetase nomenclature 1959 courage scientists referencing ACSL to adhere to the newnomenclature.NOMENCLATUREThe HGNC and MGNC have chosen ACS as the familyroot name: synthetase, rather than ligase or synthase, wasselected for the activity and acyl-CoA for the product. Syn-thetase refers to a reaction that uses ATP and forms anacyl-AMP intermediate. Despite the fact that the bestknown substrates are fatty acids, the entire spectrum ofnatural and xenobiotic substrates used by ACSL and otherACS subfamilies is not fully known, but it certainly encom-passes substrates that are not fatty acids. For example, xe-nobiotic carboxylic acids (4) and bile acids (5) are sub-strates. Thus, the use of acyl-CoA is preferred because itdoes not limit ACS substrates to fatty acids.The ACS family includes enzymes that prefer short-,medium-, long-, or very long-chain fatty acids as substrates.Although related family members exhibit considerableoverlap in their use of fatty acids of similar chain lengths,differences in the amino acid sequences of the AMP/ATPand fatty acid binding motifs distinguish subfamilies previ-ously designated as acetyl-CoA synthetase, medium-chainacyl-CoA synthetase, long-chain acyl-CoA synthetase, verylong-chain acyl-CoA synthetase, bubblegum (lipidosin),and scFat2p (6). Earlier studies used the term LACS (long-chain ACS) to distinguish ACS isoforms that act on long-chain fatty acids; however, the revised nomenclature rec-ommends a hierarchical approach with ACS as the rootsymbol followed by a letter to specify the length of fattyacid acted upon. The HGNC and MGNC have approvedthe ACSL mammalian gene nomenclature.As standard guidelines for human and rodent gene no-menclature, the human symbols are entirely capitalized(e.g.,  ACSS ,  ACSM ,  ACSL ) and the rodent symbols are low-ercase with the exception of the first letter (e.g.,  Acss , Acsm ,  Acsl ) (7). The HGNC recommends that gene and al-lele symbols be italicized and protein symbols be repre-sented in nonitalicized fonts. Italics need not be used ingene catalogs. Proteins are shown in uppercase letters. Todistinguish between mRNA, genomic DNA, and cDNA,the relevant prefix should be written in parentheses: (mRNA) ACSL1 , (gDNA)  ACSL1 , (cDNA)  ACSL1 .ORTHOLOGYImproper designation of  ACSL1 , the first cloned humanACSL family member, has caused considerable confusion.Although two separate genes were originally reported toencode FACL1 (fatty acid-CoA ligase) and FACL2 (8, 9), itwas subsequently discovered that  FACL1  and  FACL2  arethe same gene. Therefore, the revised nomenclature sys-tem now identifies  FACL1 / FACL2  as human  ACSL1 . As aconsequence of the original human nomenclature, thepreviously reported  FACL2  was not orthologous to rodent ACS2 . To correct this problem, the former rodent  ACS2 has been redesignated as  Acsl6  because it shares highestsequence identity with human  ACSL6  [originally charac-terized as  LACS5  (10)], as shown in  Table 1 . Hence, ac-cording to the revised nomenclature system, there is no ACSL2  in humans or in rodents.SPLICE VARIANTSThe  ACSL3 ,  ACSL4 ,  ACSL5 , and  ACSL6  genes encodemRNAs and proteins that have splice variants. The human ACSL3  gene encodes two transcripts with varying 5   un-translated regions, ACSL3 variant 1 ( ACSL3_v1 ) and TABLE 1. Revised nomenclature for the long-chain acyl-CoA synthetase gene family Approved Nomenclature(Chromosome Location)PreviousNomenclatureand AliasesGene and Protein Sequences Gene and Protein SequencesHuman Rat Mouse Human Rat Mouse ACSL1(4q34-q35)Acsl1(16q11)Acsl1(8 B1.1)FACL1, FACL2,LACS, LACS1,ACS1, LACS2NM_001995, NP_001986 NM_012820,NP_036952NM_007981,NP_032007ACSL3(2q34-q35)Acsl3(9q33)Acsl3(1 C4)FACL3, ACS3,PRO2194variant 1 / variant 2:NM_004457 / NM_203372NP_004448 / NP_976251.1NM_057107,NP_476448XM_129894,XP_129894ACSL4(Xq22.3-q23)Acsl4(Xq14)Acsl4(X F1)FACL4, ACS4,LACS4, MRX63variant 1 / variant 2:NM_004458 / NM_022977NP_004449 / NP_075266NM_053623,NP_446075NM_019477,NP_062350ACSL5(10q25.1-q25.2)Acsl5(1q55)Acsl5(19 D2)FACL5, ACS2,ACS5variant 1 / variant 2 / variant 3:NM_016234 / NM_203379 / NM_203380NP_057318 / NP_976313 / NP_976314NM_053607,NP_446059BC031544,AAH31544ACSL6(5q31)Acsl6(10q22)Acsl6(11 B1.3)FACL6, ACS2,LACS2, LACS5,KIAA0837variant 1 / variant 2:NM_015256 / AB020644NP_056071 / BAA74860variant 1 / variant 2:NM_130739 / —NP_570095 / AY625254variant 1 / variant 2:NM_144823 / AY167035NP_659072 / AAO38689This table is a modified version of that posted on the Human Genome Nomenclature Committee website (http://www.gene.ucl.ac.uk/nomenclature/genefamily/acs.html). The final nomenclature for the other ACS subfamilies is still under consideration. 1960 Journal of Lipid Research Volume 45, 2004 ACSL3_v2  (Table 1). Both transcripts encode the sameACSL3 protein. Human ACSL3 is homologous to rat andmouse ACSL3. Likewise, human ACSL4 is homologous torat and mouse ACSL4. In humans, two splice variants ofACSL4 have been demonstrated (11). Compared with ACSL4_v1 ,  ACSL4_v2  contains an earlier in-frame startcodon that encodes a hydrophobic N terminus that is41 amino acids longer. Human ACSL5, which is homolo-gous to rat and mouse ACSL5, has three splice variants. ACSL5_v1  encodes a protein with a 56 amino acid longerN terminus (ACSL5a) compared with the protein en-coded by both  ACSL5_v2  and  ACSL5_v3 , which encodethe same shorter protein (ACSL5b). Splice variants of ACSL6  have been identified in humans and rodents (un-published observations). The  ACSL6_v1  and  ACSL6_v2 transcripts of human  ACSL6  differ in amino acid residues306–331 because they are encoded by exon 14 and exon13, respectively, as a result of alternative exon use.The numerous examples of  ACSL  genes encoding multi-ple proteins having different N-terminal and/or internalregions suggest that additional splice variants will be identi-fied. The HGNC recommends that new variants of  ACSL1–6  or  Acsl1–6  should be named splice variants of a gene(e.g.,  ACSL5_v4 ) if they use some of the same exons as anexisting ACSL isoform (http://www.gene.ucl.ac.uk/nomenclature/guidelines.html). For genes with multiplepromoters, the alternative promoters are designated by the ad-dition of the lowercase letters “pr” (e.g., symbol:  ACSL6_pr1 ;name: long-chain acyl-CoA synthetase 6, promoter 1). Proteinstranslated from mRNA splice variants may be distinguished bylowercase suffixes (e.g., ACSL5a and ACSL5b).OTHER ACS FAMILY MEMBERSIt should be noted that proteins of the family previouslynamed very long-chain ACS (VLCS) (6) are also known asfatty acid transport proteins (FATPs). These are includedin the superfamily of proteins encoded by members of thesolute carrier gene family, whose currently approved genesymbols are  SLC27A1–6  (12). The VLCS/FATPs also haveacyl-CoA synthetase enzymatic activity (13–16). Thus, theseproteins may play a dual role in the transport and esterifi-cation of their substrates.Some amino acid sequences are shared between ACSLsubfamily members and other enzymes, such as acetyl-CoAsynthetase, bubblegum, and scFat2p, and related proteins(6). As yet, a standardized nomenclature has not been for-mulated for these other enzymes or for the yeast and bacte-rial ACS families. Each member of the extended ACS fam-ily has the ATP/AMP binding motif that is a hallmark ofadenylate-forming enzymes as well as a fatty acid bindingmotif defined in the bacterial homolog FadD (17).CONCLUSIONSPrevious publications have used a multitude of namesfor members of the ACSL family, which has led to confu-sion among investigators. Implementation of the revisednomenclature proposed here for the mammalian ACSLgene family will reduce disparities and render our litera-ture more accessible to us as well as to those outside thefield.The use of  ACSS  and  ACSM  root symbols for the acetyl-CoA and medium-chain acyl-CoA synthetases, respectively,should also be considered. The VLCS/FATP/ SLC27A1–6 and the bubblegum/lipidosin subfamily members use assubstrates long-chain and very long-chain fatty acids and/or bile acids; thus, it is not yet clear what prefix should beused to designate these enzymes. Further consultation isneeded among scientists who study these proteins. Wepropose that those working on ACS genes in other organ-isms also consider adopting a similar nomenclature. This project was supported in part by the Austrian ScienceFoundation FWF P14163-MOB (J.B.); the National Institutes ofHealth: DK-53189 (D.A.B.), HL-076719 (K.E.B.), GM-56850(P.N.B), DK-59935 (R.A.C.), DK-60369 (S.A.F.), P30 HG-00330(L.J.M.), P30 ES-06096 (D.W.N.), DK-066336 and DK-56339(A.S.), EY-11490 (V.V.), and NS-37351 (P.A.W.); and the Ameri-can Heart Association: North East Affiliate 0151215T (C.C.DR)and 0265311Y (A.S). The work of the Human Genome Nomen-clature Committee is supported by National Institutes of Healthcontract N01-LM-9-3533, the UK Medical Research Council,and the Wellcome Trust. REFERENCES 1. Cleland, W. W. 1963. The kinetics of enzyme-catalyzed reactionswith two or more substrates or products. I. Nomenclature and rateequations.  Biochim. Biophys. Acta.   67:  104–137.2. Bar-Tana, J., G. Rose, R. Brandes, and B. Shapiro. 1973. 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Revised nomenclature for the mammalian long-chain acyl-CoA synthetase gene family: TABLE 1.

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Revised nomenclature for the mammalian long-chain acyl-CoA synthetase gene family: TABLE 1.

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