C9orf3

Chromosome 9 open reading frame 3 (C9ORF3) also known as aminopeptidase O (APO) is an enzyme which in humans is encoded by the C9ORF3 gene.[4] The protein encoded by this gene is an aminopeptidase which is most closely related in sequence to leukotriene A4 hydrolase (LTA4H).[5] APO is a member of the M1 metalloproteinase family.[6][7]

AOPEP
Identifiers
AliasesAOPEP, chromosome 9 open reading frame 3, AP-O, APO, C90RF3, ONPEP, aminopeptidase O (putative), C9orf3
External IDsMGI: 1919311 HomoloGene: 66273 GeneCards: AOPEP
Gene location (Human)
Chr.Chromosome 9 (human)[1]
Band9q22.32Start94,726,701 bp[1]
End95,087,218 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

84909

72061

Ensembl

ENSG00000148120

n/a

UniProt

Q8N6M6

Q8BXQ6

RefSeq (mRNA)

NM_001193329
NM_001193330
NM_001193331
NM_032823

NM_001289924
NM_001289926
NM_028079

RefSeq (protein)

NP_001180258
NP_001180260
NP_116212

NP_001276853
NP_001276855

Location (UCSC)Chr 9: 94.73 – 95.09 Mbn/a
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

The C9ORF3 aminopeptidase enzyme contains the following domains:[5]

Function

The C9ORF3 aminopeptidase cleaves the N-terminal amino acid from polypeptides and shows a strong preference for peptides in which the N-terminus is arginine and to a lesser extent asparagine. Furthermore, the activity of the enzyme is inhibited by o-phenanthroline, a metalloprotease inhibitor and by arphamenine A, a potent inhibitor of aminopeptidases such as LTA4H. Also able to cleave angiotensin III to generate angiotensin IV, a bioactive peptide of the renin–angiotensin pathway.[5]

Due to its aminopeptidase activity this enzyme may play a role in the proteolytic processing of bioactive peptides in those tissues where it is expressed.

Tissue distribution

C9ORF3 Messenger RNA has been detected in human pancreas, placenta, liver, testis, and heart. The expression in the heart suggests this enzyme may also play a role in the regulating the physiology of cardiac muscle.[5] Several ApO isoforms are expressed predominantly in blood vessels suggesting that ApO plays a role in vascular cell biology.[6]

Clinical significance

High expression levels of C9ORF3 is positively correlated with maximal oxygen uptake (VO2 max) and the amount of "slow-twitch" type 1 muscle fibers.[8]

References
  1. GRCh38: Ensembl release 89: ENSG00000148120 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. Strausberg RL, Feingold EA, Grouse LH, et al. (December 2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
  5. Díaz-Perales A, Quesada V, Sánchez LM, Ugalde AP, Suárez MF, Fueyo A, López-Otín C (April 2005). "Identification of human aminopeptidase O, a novel metalloprotease with structural similarity to aminopeptidase B and leukotriene A4 hydrolase". J. Biol. Chem. 280 (14): 14310–7. doi:10.1074/jbc.M413222200. PMID 15687497. (Retracted, see doi:10.1074/jbc.w118.007327. If this is an intentional citation to a retracted paper, please replace {{Retracted}} with {{Retracted|intentional=yes}}.)
  6. Axton R, Wallis JA, Taylor H, Hanks M, Forrester LM (March 2008). "Aminopeptidase O contains a functional nucleolar localization signal and is implicated in vascular biology". J. Cell. Biochem. 103 (4): 1171–82. doi:10.1002/jcb.21497. PMID 17803194. S2CID 11365605.
  7. Albiston AL, Ye S, Chai SY (October 2004). "Membrane bound members of the M1 family: more than aminopeptidases". Protein Pept. Lett. 11 (5): 491–500. doi:10.2174/0929866043406643. PMID 15544570.
  8. Parikh H, Nilsson E, Ling C, Poulsen P, Almgren P, Nittby H, Eriksson KF, Vaag A, Groop LC (June 2008). "Molecular correlates for maximal oxygen uptake and type 1 fibers". Am. J. Physiol. Endocrinol. Metab. 294 (6): E1152–9. doi:10.1152/ajpendo.90255.2008. PMID 18445752.


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