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Aliases C9orf3, chromosome 9 open reading frame 3, AOPEP, AP-O, APO, C90RF3, ONPEP
External IDs MGI: 1919311 HomoloGene: 66273 GeneCards: C9orf3
Species Human Mouse
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC) Chr 9: 94.73 – 95.09 Mb Chr 13: 62.96 – 63.33 Mb
PubMed search [1] [2]
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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.[3] The protein encoded by this gene is an aminopeptidase which is most closely related in sequence to leukotriene A4 hydrolase (LTA4H).[4] APO is a member of the M1 metalloproteinase family.[5][6]


The C9ORF3 aminopeptidase enzyme contains the following domains:[4]


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.[4]

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[edit]

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.[4] Several ApO isoforms are expressed predominantly in blood vessels suggesting that ApO plays a role in vascular cell biology.[5]

Clinical significance[edit]

High expression levels of C9ORF3 is positively correlated with maximal oxygen uptake (VO2 max) and the amount of "slow-twitch" type 1 muscle fibers.[7]


  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ 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. PMC 139241Freely accessible. PMID 12477932. doi:10.1073/pnas.242603899. 
  4. ^ a b c d 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. PMID 15687497. doi:10.1074/jbc.M413222200. 
  5. ^ a b 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. PMID 17803194. doi:10.1002/jcb.21497. 
  6. ^ 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. PMID 15544570. doi:10.2174/0929866043406643. 
  7. ^ 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. PMID 18445752. doi:10.1152/ajpendo.90255.2008. 

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