Volume 3 Supplement 6

Proceedings of the 2007 and 2008 Symposia on Protein N-terminal Acetylation

Open Access

A synopsis of eukaryotic Nα-terminal acetyltransferases: nomenclature, subunits and substrates

BMC Proceedings20093(Suppl 6):S2

DOI: 10.1186/1753-6561-3-S6-S2

Published: 4 August 2009


We have introduced a consistent nomenclature for the various subunits of the NatA-NatE N-terminal acetyltransferases from yeast, humans and other eukaryotes.


N-terminal acetylation has been extensively studied in yeast and humans and represents one of the most common protein modifications in eukaryotes, occurring on approximately 57% of yeast proteins and 84% human proteins [1], although it is rare in prokaryotes. Eukaryotic proteins initiate with methionine residues, which are cleaved from nascent chains if the penultimate residue has a radius of gyration of 1.29 Å or less [2]. N-terminal acetylation subsequently occurs on certain of the proteins, either containing or lacking the methionine residue, as depicted in Fig. 1. The salient features of N-terminal acetylation are summarized in Table 1 and Fig. 2. Detailed reviews on the N-terminal acetyltransferases have appeared [37], and the N-terminal acetylation status of 742 human and 616 yeast protein N-termini have been compiled [1]. The wide range and diversity of substrates is due in part to the large number of different N-terminal acetylating enzymes, NatA-NatE. The sequence requirements for N-terminal acetylation vary with the N-terminal acetyltransferase. Only two amino acid residues, Met-Asn-, Met-Asp-, or Met-Glu-, are required for at least partial N-terminal acetylation by NatB [1, 8]. On the other hand, 30 to 50 specific amino acids are required for N-terminal acetylation by NatD [9]. Each of the three major N-terminal acetyltransferases, NatA, NatB and NatC, contain a catalytic subunit, and one or two auxiliary subunits (Table 1). The sequence and functions of the yeast and human orthologous subunits are obviously related. A yeast ard1nat1-Δ strain was phenotypically complemented by hARD1 hNAT1, suggesting that yNatA and hNatA are similar. However, heterologous combinations, hARD1 yNAT1 and yARD1 hNAT1, were not functional in yeast, suggesting significant structural subunit differences between the species [1].
Table 1

Revised nomenclature for N-terminal acetyltransferases









   Catalytic subunit






   Auxiliary subunit










   Catalytic subunit






   Auxiliary subunit








Number of yeast substrates





























------------2 to 8 amino acids-----------

30–50 a. a


Naa50p is inferred to be an N-terminal acetyltransferase because of its sequence homology to known NATs.

* Acetylation occurs at least partially on all proteins with Met-Glu-, Met-Asp- and Met-Asn- termini, but only on subclasses of proteins with the other termini.

† Naa15p may be an auxiliary subunit of NatE, as well as an auxiliary subunit of NatA.

‡ Found in humans but not yeast (see Figure 2 legend).

¶One example found in yeast (see Figure 2 legend).

Figure 1

A summary of the major pathways of N -terminal processing in eukaryotes, showing the four different termini. 1: Uncleaved and unacetylated Met-Xxx- N-termini; 2: Cleaved and unacetylated Xxx-N-termini; 3: Uncleaved and NatB/NatC acetylated Ac-Met-Xxx- N-termini; 4: Cleaved and NatA acetylated Ac-Xxx-N-termini. See Table 1 and Figure 2 for more detail.

Figure 2

The major pathways of N -terminal processing in eukaryotes. Two methionine aminopeptidases (MAP), Map1p and Map2p, cleave N-terminal methionine residues that have small side chains (glycine, alanine, serine, cysteine, threonine, proline, and valine), although methionine is retained on some proteins having penultimate residues of valine. Subsequently, NatA, NatB, and NatC acetylate specific sequences as shown in the figure and in Table 1. Acetylation occurs at least partially on all proteins with Met-Glu-, Met-Asp- and Met-Asn- termini, but only on subclasses of proteins with the other termini. For example, acetylation occurs at least partially on 43% of proteins in yeast and on 96% of proteins in humans with Ala- termini. In addition, Ac-Cys-, Ac-Val-, Ac-Met-Met-, and Ac-Met-Lys- termini occurs on some proteins from humans but not from yeast; it is unknown which NATs are responsible for Ac-Cys-, Ac-Met-Met-, and Ac-Met-Lys- acetylations.


During a recent international meeting on N-terminal acetylation, it was pointed out that there is critical need to revise the gene symbols encoding the N-terminal acetyltransferases. The main reason for changing the nomenclature is so that each of the orthologous genes from different species would have the same name. Furthermore, orthologous genes were assigned not only by similarity of their sequences, but also by their action on the same set of proteins. Yeast NatA and human NatA were shown to acetylate the same set proteins by comparing a normal yeast strain with the mutant naa10naa15-ΔhNAA10 hNAA15 [1].

The use of the different symbols NAT, ARD, MDM, and MAK is confusing, and does not provide useful information, especially when applied to human NATs. We believe it can be misleading to assign a gene symbol based on one phenotype of a mutant when a large number of proteins are affected, and when the mutant is pleiotropic.

Most importantly, different orthologous genes should have different names. The symbols NAT1, NAT2 and NAT3 denote human genes encoding arylamine N-acetyltransferases, which are distinct from N-terminal acetyltransferases [10]. On the other hand, NCBI has designated the human homologue of the yeast NAT genes as follows: yNAT1 designated as hNARG1; yNAT3 designated as hNAT5; and yNAT5 designated as hNAT13. Also, ARD1 is used to describe the ADP-ribosylation factor domain protein 1 [11].

Therefore, in this paper we have introduced a new nomenclature for protein N-terminal acetyltransferases in eukaryotes (Table 1). It is important to note that NAA (Nα acetyltransferases) is not used to designate any other gene in yeast or higher eukaryotes. We have assigned each of the subunits of the NatA-NatE complexes a Naa symbol, as presented in Table 1. We have also recommended a nomenclature for paralogs of human NatA complexes containing either Naa10p or Naa11p in combination with either Naa15p or Naa16p (Table 2). The revised symbols, along with synonyms from yeast and humans, are presented in Table 3. Clearly, this revised nomenclature will greatly diminish the confusion in describing orthologous subunits from different species.
Table 2




Catalytic subunit Naa10p, Naa11p


NatA(10+15); NatA(10+16); NatA(11+15); NatA(11+16)

Auxiliary subunit Naa15p, Naa16p


Almost all human NAT subunit genes encode alternative splicing isoforms whose functions are in question, and are not considered here.

Table 3



Accession no.


Primary name






Ard1p; TE2















Nat2p; NARG1L



[20, 21]


Nat3p; hNat5p



[8, 22, 23]


Mdm20p; p120



[8, 23]


Mak3p; hNat12p





Mak10p; hEGAP



[24, 25, 27]


Mak31p; hLsm8p



[24, 25, 27]


Nat4p; hNat11p





Nat5p; hNat13p; San




An example of standard symbols: Protein, Naa10p; Gene, NAA10; Deleted gene, naa10-Δ. hNaa10p, human; yNaa10p, yeast (S. cerevisiae); mNaa10p, mouse.



This work was supported by the Norwegian Health region West (to T.A.), the Norwegian Research Council (to T.A), and the National Institutes of Health Grant R01 GM12702 (to F.S.).

This article has been published as part of BMC Proceedings Volume 3 Supplement 6, 2009: Proceedings of the 2007 and 2008 Symposia on Protein N-terminal Acetylation. The full contents of the supplement are available online at http://www.biomedcentral.com/1753-6561/3?issue=S6

Authors’ Affiliations

Department of Biochemistry and Biophysics, University of Rochester Medical Center
Department of Molecular Biology, University of Bergen
Department of Surgical Sciences, University of Bergen
Department of Surgery, Haukeland University Hospital


  1. Arnesen T, Van Damme P, Polevoda B, Helsens K, Evjenth R, Colaert N, et al: Proteomics analyses reveal the evolutionary conservation and divergence of N-terminal acetyltransferases from yeast and humans. Proc Natl Acad Sci USA. 2009, 106: 8157-8162. 10.1073/pnas.0901931106.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Sherman F, Stewart JW, Tsunasawa S: Methionine or not methionine at the beginning of a protein. Bioessays. 1985, 3: 27-31. 10.1002/bies.950030108.View ArticlePubMedGoogle Scholar
  3. Arnesen T, Thompson PR, Varhaug JE, Lillehaug JR: The Protein Acetyltransferase ARD1: A Novel Cancer Drug Target?. Curr Cancer Drug Targets. 2008, 8: 545-553. 10.2174/156800908786241113.View ArticlePubMedGoogle Scholar
  4. Gromyko D, Starheim KK, Velde R, Varhaug JE, Arnesen T: Human N-terminal acetyltransferases: Identification and biological significance. BMC Proc. 2009, 3 (Suppl 3): S3-10.1186/1753-6561-3-s3-o3.PubMed CentralView ArticlePubMedGoogle Scholar
  5. Polevoda B, Norbeck J, Takakura H, Blomberg A, Sherman F: Identification and specificities of N-terminal acetyltransferases from Saccharomyces cerevisiae. EMBO J. 1999, 18: 6155-6168. 10.1093/emboj/18.21.6155.PubMed CentralView ArticlePubMedGoogle Scholar
  6. Polevoda B, Sherman F: N-terminal acetyltransferases and sequence requirements for N-terminal acetylation of eukaryotic proteins. J Mol Biol. 2003, 325: 595-622. 10.1016/S0022-2836(02)01269-X.View ArticlePubMedGoogle Scholar
  7. Polevoda B, Sherman F: Composition and function of the eukaryotic N-terminal acetyltransferase subunits. Biochemical and Biophysical Research Communications. 2003, 308: 1-11. 10.1016/S0006-291X(03)01316-0.View ArticlePubMedGoogle Scholar
  8. Polevoda B, Cardillo TS, Doyle TC, Bedi GS, Sherman F: Nat3p and Mdm20p are required for function of yeast NatB Nalpha-terminal acetyltransferase and of actin and tropomyosin. J Biol Chem. 2003, 278: 30686-30697. 10.1074/jbc.M304690200.View ArticlePubMedGoogle Scholar
  9. Polevoda B, Hoskins J, Sherman F: Properties of Nat4, an N{alpha}-Acetyltransferase of Saccharomyces cerevisae that Modifies N termini of Histones H2A and H4. Mol Cell Biol. 2009Google Scholar
  10. Vagena E, Fakis G, Boukouvala S: Arylamine N-acetyltransferases in prokaryotic and eukaryotic genomes: a survey of public databases. Curr Drug Metab. 2008, 9: 628-660. 10.2174/138920008785821729.View ArticlePubMedGoogle Scholar
  11. Vichi A, Payne DM, Pacheco-Rodriguez G, Moss J, Vaughan M: E3 ubiquitin ligase activity of the trifunctional ARD1 (ADP-ribosylation factor domain protein 1). Proc Natl Acad Sci USA. 2005, 102: 1945-1950. 10.1073/pnas.0409800102.PubMed CentralView ArticlePubMedGoogle Scholar
  12. Arnesen T, Anderson D, Baldersheim C, Lanotte M, Varhaug JE, Lillehaug JR: Identification and characterization of the human ARD1-NATH protein acetyltransferase complex. Biochem J. 2005, 386: 433-443. 10.1042/BJ20041071.PubMed CentralView ArticlePubMedGoogle Scholar
  13. Tribioli C, Mancini M, Plassart E, Bione S, Rivella S, Sala C, et al: Isolation of new genes in distal Xq28: transcriptional map and identification of a human homologue of the ARD1 N-acetyl transferase of Saccharomyces cerevisiae. Hum Mol Genet. 1994, 3: 1061-1067. 10.1093/hmg/3.7.1061.View ArticlePubMedGoogle Scholar
  14. Whiteway M, Szostak JW: The ARD1 gene of yeast functions in the switch between the mitotic cell cycle and alternative developmental pathways. Cell. 1985, 43: 483-492. 10.1016/0092-8674(85)90178-3.View ArticlePubMedGoogle Scholar
  15. Arnesen T, Betts MJ, Pendino F, Liberles DA, Anderson D, Caro J, et al: Characterization of hARD2, a processed hARD1 gene duplicate, encoding a human protein N-alpha-acetyltransferase. BMC Biochem. 2006, 7: 13-10.1186/1471-2091-7-13.PubMed CentralView ArticlePubMedGoogle Scholar
  16. Fluge O, Bruland O, Akslen LA, Varhaug JE, Lillehaug JR: NATH, a novel gene overexpressed in papillary thyroid carcinomas. Oncogene. 2002, 21: 5056-5068. 10.1038/sj.onc.1205687.View ArticlePubMedGoogle Scholar
  17. Gendron RL, Adams LC, Paradis H: Tubedown-1, a novel acetyltransferase associated with blood vessel development. Dev Dyn. 2000, 218: 300-315. 10.1002/(SICI)1097-0177(200006)218:2<300::AID-DVDY5>3.0.CO;2-K.View ArticlePubMedGoogle Scholar
  18. Mullen JR, Kayne PS, Moerschell RP, Tsunasawa S, Gribskov M, Colavito-Shepanski M, et al: Identification and characterization of genes and mutants for an N-terminal acetyltransferase from yeast. EMBO J. 1989, 8: 2067-2075.PubMed CentralPubMedGoogle Scholar
  19. Park EC, Szostak JW: ARD1 and NAT1 proteins form a complex that has N-terminal acetyltransferase activity. EMBO J. 1992, 11: 2087-2093.PubMed CentralPubMedGoogle Scholar
  20. Sugiura N, Adams SM, Corriveau RA: An evolutionarily conserved N-terminal acetyltransferase complex associated with neuronal development. J Biol Chem. 2003, 278: 40113-40120. 10.1074/jbc.M301218200.View ArticlePubMedGoogle Scholar
  21. Arnesen T, Gromyko D, Kagabo D, Betts MJ, Starheim KK, Varhaug JE, et al: A novel human NatA N-alpha-terminal acetyltransferase complex: hNaa16p-hNaa10p (hNat2-hArd1). BMC Biochem. 2009, 10: 15-10.1186/1471-2091-10-15.PubMed CentralView ArticlePubMedGoogle Scholar
  22. Ametzazurra A, Larrea E, Civeira MP, Prieto J, Aldabe R: Implication of human N-alpha-acetyltransferase 5 in cellular proliferation and carcinogenesis. Oncogene. 2008, 27: 7296-7306. 10.1038/onc.2008.332.View ArticlePubMedGoogle Scholar
  23. Starheim KK, Arnesen T, Gromyko D, Ryningen A, Varhaug JE, Lillehaug JR: Identification of the human N(alpha)-acetyltransferase complex B (hNatB): a complex important for cell-cycle progression. Biochem J. 2008, 415: 325-331. 10.1042/BJ20080658.View ArticlePubMedGoogle Scholar
  24. Polevoda B, Sherman F: NatC Nalpha-terminal acetyltransferase of yeast contains three subunits, Mak3p, Mak10p, and Mak31p. J Biol Chem. 2001, 276: 20154-20159. 10.1074/jbc.M011440200.View ArticlePubMedGoogle Scholar
  25. Starheim KK, Gromyko D, Evjenth R, Ryningen A, Varhaug JE, Lillehaug JR, et al: Knockdown of the Human N{alpha}-Terminal Acetyltransferase Complex C (hNatC) Leads to p53-Dependent Apoptosis and Aberrant hArl8b Localization. Mol Cell Biol. 2009, 29: 3569-3581. 10.1128/MCB.01909-08.PubMed CentralView ArticlePubMedGoogle Scholar
  26. Tercero JC, Wickner RB: MAK3 encodes an N-acetyltransferase whose modification of the L-A gag NH2 terminus is necessary for virus particle assembly. J Biol Chem. 1992, 267: 20277-20281.PubMedGoogle Scholar
  27. Wenzlau JM, Garl PJ, Simpson P, Stenmark KR, West J, Artinger KB, et al: Embryonic growth-associated protein is one subunit of a novel N-terminal acetyltransferase complex essential for embryonic vascular development. Circ Res. 2006, 98: 846-855. 10.1161/01.RES.0000214539.86593.7a.View ArticlePubMedGoogle Scholar
  28. Song OK, Wang X, Waterborg JH, Sternglanz R: An Nalpha-acetyltransferase responsible for acetylation of the N-terminal residues of histones H4 and H2A. J Biol Chem. 2003, 278: 38109-38112. 10.1074/jbc.C300355200.View ArticlePubMedGoogle Scholar
  29. Arnesen T, Anderson D, Torsvik J, Halseth HB, Varhaug JE, Lillehaug JR: Cloning and characterization of hNAT5/hSAN: an evolutionarily conserved component of the NatA protein N-alpha-acetyltransferase complex. Gene. 2006, 371: 291-295. 10.1016/j.gene.2005.12.008.View ArticlePubMedGoogle Scholar
  30. Gautschi M, Just S, Mun A, Ross S, Rucknagel P, Dubaquie Y, et al: The yeast N(alpha)-acetyltransferase NatA is quantitatively anchored to the ribosome and interacts with nascent polypeptides. Mol Cell Biol. 2003, 23: 7403-7414. 10.1128/MCB.23.20.7403-7414.2003.PubMed CentralView ArticlePubMedGoogle Scholar
  31. Williams BC, Garrett-Engele CM, Li Z, Williams EV, Rosenman ED, Goldberg ML: Two putative acetyltransferases, san and deco, are required for establishing sister chromatid cohesion in Drosophila. Curr Biol. 2003, 13: 2025-2036. 10.1016/j.cub.2003.11.018.View ArticlePubMedGoogle Scholar


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