NAT_MYCTU
ID NAT_MYCTU Reviewed; 283 AA.
AC P9WJI5; L0TCY1; P0A5L8; P96848;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 25-MAY-2022, entry version 38.
DE RecName: Full=Arylamine N-acetyltransferase {ECO:0000303|PubMed:9973365};
DE Short=NAT {ECO:0000303|PubMed:9973365};
DE EC=2.3.1.5 {ECO:0000269|PubMed:18795795, ECO:0000269|PubMed:19014350};
DE AltName: Full=TBNAT {ECO:0000303|PubMed:18795795, ECO:0000303|PubMed:19014350};
GN Name=nat {ECO:0000303|PubMed:9973365}; Synonyms=nhoA, tbnat;
GN OrderedLocusNames=Rv3566c; ORFNames=MTCY06G11.13c;
OS Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
OC Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
OC Mycobacterium; Mycobacterium tuberculosis complex.
OX NCBI_TaxID=83332;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=9634230; DOI=10.1038/31159;
RA Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M., Harris D.E.,
RA Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, Tekaia F., Badcock K.,
RA Basham D., Brown D., Chillingworth T., Connor R., Davies R.M., Devlin K.,
RA Feltwell T., Gentles S., Hamlin N., Holroyd S., Hornsby T., Jagels K.,
RA Krogh A., McLean J., Moule S., Murphy L.D., Oliver S., Osborne J.,
RA Quail M.A., Rajandream M.A., Rogers J., Rutter S., Seeger K., Skelton S.,
RA Squares S., Squares R., Sulston J.E., Taylor K., Whitehead S.,
RA Barrell B.G.;
RT "Deciphering the biology of Mycobacterium tuberculosis from the complete
RT genome sequence.";
RL Nature 393:537-544(1998).
RN [2]
RP SEQUENCE REVISION.
RX PubMed=12368430; DOI=10.1099/00221287-148-10-2967;
RA Camus J.-C., Pryor M.J., Medigue C., Cole S.T.;
RT "Re-annotation of the genome sequence of Mycobacterium tuberculosis
RT H37Rv.";
RL Microbiology 148:2967-2973(2002).
RN [3]
RP FUNCTION.
RX PubMed=9973365; DOI=10.1128/jb.181.4.1343-1347.1999;
RA Payton M.A., Auty R., Delgoda R.T., Everitt M., Sim E.;
RT "Cloning and characterization of arylamine N-acetyltransferase genes from
RT Mycobacterium smegmatis and Mycobacterium tuberculosis: increased
RT expression results in isoniazid resistance.";
RL J. Bacteriol. 181:1343-1347(1999).
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, SUBSTRATE SPECIFICITY, BIOPHYSICOCHEMICAL
RP PROPERTIES, REACTION MECHANISM, AND ACTIVE SITE.
RC STRAIN=H37Rv;
RX PubMed=18795795; DOI=10.1021/bi800398c;
RA Sikora A.L., Frankel B.A., Blanchard J.S.;
RT "Kinetic and chemical mechanism of arylamine N-acetyltransferase from
RT Mycobacterium tuberculosis.";
RL Biochemistry 47:10781-10789(2008).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, SUBSTRATE SPECIFICITY, AND BIOPHYSICOCHEMICAL
RP PROPERTIES.
RX PubMed=19014350; DOI=10.1042/bj20082011;
RA Lack N.A., Kawamura A., Fullam E., Laurieri N., Beard S., Russell A.J.,
RA Evangelopoulos D., Westwood I., Sim E.;
RT "Temperature stability of proteins essential for the intracellular survival
RT of Mycobacterium tuberculosis.";
RL Biochem. J. 418:369-378(2009).
RN [6]
RP IDENTIFICATION AS A DRUG TARGET [LARGE SCALE ANALYSIS].
RX PubMed=19099550; DOI=10.1186/1752-0509-2-109;
RA Raman K., Yeturu K., Chandra N.;
RT "targetTB: a target identification pipeline for Mycobacterium tuberculosis
RT through an interactome, reactome and genome-scale structural analysis.";
RL BMC Syst. Biol. 2:109-109(2008).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=21969609; DOI=10.1074/mcp.m111.011627;
RA Kelkar D.S., Kumar D., Kumar P., Balakrishnan L., Muthusamy B., Yadav A.K.,
RA Shrivastava P., Marimuthu A., Anand S., Sundaram H., Kingsbury R.,
RA Harsha H.C., Nair B., Prasad T.S., Chauhan D.S., Katoch K., Katoch V.M.,
RA Kumar P., Chaerkady R., Ramachandran S., Dash D., Pandey A.;
RT "Proteogenomic analysis of Mycobacterium tuberculosis by high resolution
RT mass spectrometry.";
RL Mol. Cell. Proteomics 10:M111.011627-M111.011627(2011).
RN [8]
RP 3D-STRUCTURE MODELING, AND DRUG RESISTANCE.
RX PubMed=21514309; DOI=10.1016/j.mrfmmm.2011.03.017;
RA Coelho M.B., Costa E.R., Vasconcellos S.E., Linck N., Ramos R.M.,
RA Amorim H.L., Suffys P.N., Santos A.R., Silva P.E., Ramos D.F., Silva M.S.,
RA Rossetti M.L.;
RT "Sequence and structural characterization of tbnat gene in isoniazid-
RT resistant Mycobacterium tuberculosis: identification of new mutations.";
RL Mutat. Res. 712:33-39(2011).
CC -!- FUNCTION: Catalyzes the transfer of the acetyl group from acetyl
CC coenzyme A to the free amino group of arylamines and hydrazines
CC (PubMed:18795795). Is able to utilize not only acetyl-CoA, but also n-
CC propionyl-CoA and acetoacetyl-CoA as acyl donors, although at a lower
CC rate (PubMed:19014350). As acetyl-CoA and propionyl-CoA are products of
CC cholesterol catabolism and the nat gene is likely present in the same
CC operon than genes involved in cholesterol degradation, this enzyme
CC could have a role in the utilization and regulation of these CoA
CC species (PubMed:19014350). {ECO:0000269|PubMed:18795795,
CC ECO:0000269|PubMed:19014350}.
CC -!- FUNCTION: It has been reported that overexpression of this enzyme may
CC be responsible for increased resistance to the front-line
CC antitubercular drug isoniazid (INH), by acetylating and hence
CC inactivating the prodrug (PubMed:9973365). However, isoniazid is an
CC extremely poor substrate for the enzyme; therefore, the expression of
CC TBNAT is unlikely to be a significant cause of isoniazid resistance in
CC M.tuberculosis (PubMed:18795795). {ECO:0000269|PubMed:18795795,
CC ECO:0000269|PubMed:9973365}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + an arylamine = an N-acetylarylamine + CoA;
CC Xref=Rhea:RHEA:16613, ChEBI:CHEBI:13790, ChEBI:CHEBI:50471,
CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57288; EC=2.3.1.5;
CC Evidence={ECO:0000269|PubMed:18795795, ECO:0000269|PubMed:19014350};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.14 mM for acetyl-CoA {ECO:0000269|PubMed:18795795};
CC KM=0.56 mM for acetyl-CoA {ECO:0000269|PubMed:19014350};
CC KM=0.29 mM for n-propionyl-CoA {ECO:0000269|PubMed:19014350};
CC KM=0.32 mM for 3-amino-4-hydroxybenzoic acid
CC {ECO:0000269|PubMed:18795795};
CC KM=0.90 mM for 4-amino-3-hydroxybenzoic acid
CC {ECO:0000269|PubMed:18795795};
CC KM=0.61 mM for hydralazine {ECO:0000269|PubMed:18795795};
CC KM=3.06 mM for 2-amino-4-methylphenol {ECO:0000269|PubMed:18795795};
CC KM=1.9 mM for 2-amino-4-chlorophenol {ECO:0000269|PubMed:18795795};
CC KM=5.79 mM for 2-aminophenol {ECO:0000269|PubMed:18795795};
CC KM=20 mM for 4-hydroxybenzhydrazide {ECO:0000269|PubMed:18795795};
CC KM=14 mM for anisidine {ECO:0000269|PubMed:18795795};
CC KM=5.0 mM for p-aminobenzoic acid {ECO:0000269|PubMed:18795795};
CC KM=14 mM for benzoic acid hydrazide {ECO:0000269|PubMed:18795795};
CC KM=11 mM for 4-methylaniline {ECO:0000269|PubMed:18795795};
CC KM=102 mM for isoniazid {ECO:0000269|PubMed:18795795};
CC KM=14 mM for nicotinic acid hydrazide {ECO:0000269|PubMed:18795795};
CC KM=6 mM for 4-chloroaniline {ECO:0000269|PubMed:18795795};
CC KM=23 mM for aniline {ECO:0000269|PubMed:18795795};
CC KM=51 mM for 4-fluoroaniline {ECO:0000269|PubMed:18795795};
CC Note=kcat is 94 sec(-1) with 3-amino-4-hydroxybenzoic acid as
CC substrate. kcat is 66 sec(-1) with 4-amino-3-hydroxybenzoic acid as
CC substrate. kcat is 44 sec(-1) with hydralazine as substrate. kcat is
CC 70 sec(-1) with 2-amino-4-methylphenol as substrate. kcat is 21 sec(-
CC 1) with 2-amino-4-chlorophenol as substrate. kcat is 51 sec(-1) with
CC 2-aminophenol as substrate. kcat is 10.9 sec(-1) with 4-
CC hydroxybenzhydrazide as substrate. kcat is 2.9 sec(-1) with anisidine
CC as substrate. kcat is 0.7 sec(-1) with p-aminobenzoic acid as
CC substrate. kcat is 1.9 sec(-1) with benzoic acid hydrazide as
CC substrate. kcat is 0.8 sec(-1) with 4-methylaniline as substrate.
CC kcat is 4.9 sec(-1) with isoniazid as substrate. kcat is 0.6 sec(-1)
CC with nicotinic acid hydrazide as substrate. kcat is 0.2 sec(-1) with
CC 4-chloroaniline as substrate. kcat is 0.28 sec(-1) with aniline as
CC substrate. kcat is 0.9 sec(-1) with 4-fluoroaniline as substrate.
CC {ECO:0000269|PubMed:18795795};
CC Temperature dependence:
CC Is thermostable. Retains >95% of its activity after incubation at 60
CC degrees Celsius for 30 minutes. {ECO:0000269|PubMed:19014350};
CC -!- SUBUNIT: Homodimer and homotetramer. {ECO:0000250|UniProtKB:O86309}.
CC -!- MISCELLANEOUS: Was identified as a high-confidence drug target.
CC {ECO:0000305|PubMed:19099550}.
CC -!- MISCELLANEOUS: Reactions proceed via a bi-bi ping-pong kinetic
CC mechanism. {ECO:0000269|PubMed:18795795}.
CC -!- MISCELLANEOUS: Resistance to the antitubercular drug isoniazid (INH)
CC has been associated to mutations in this gene in some INH-resistant
CC clinical isolates of M.tuberculosis. {ECO:0000269|PubMed:21514309}.
CC -!- SIMILARITY: Belongs to the arylamine N-acetyltransferase family.
CC {ECO:0000305}.
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DR EMBL; AL123456; CCP46388.1; -; Genomic_DNA.
DR RefSeq; WP_003419364.1; NZ_NVQJ01000014.1.
DR RefSeq; YP_177989.1; NC_000962.3.
DR AlphaFoldDB; P9WJI5; -.
DR SMR; P9WJI5; -.
DR STRING; 83332.Rv3566c; -.
DR DrugBank; DB00515; Cisplatin.
DR DrugBank; DB00951; Isoniazid.
DR DrugBank; DB01582; Sulfamethazine.
DR PaxDb; P9WJI5; -.
DR GeneID; 888005; -.
DR KEGG; mtu:Rv3566c; -.
DR TubercuList; Rv3566c; -.
DR eggNOG; COG2162; Bacteria.
DR OMA; CYEHNTL; -.
DR PhylomeDB; P9WJI5; -.
DR BRENDA; 2.3.1.5; 3445.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005886; C:plasma membrane; HDA:MTBBASE.
DR GO; GO:0004060; F:arylamine N-acetyltransferase activity; IDA:MTBBASE.
DR GO; GO:0046677; P:response to antibiotic; IEA:UniProtKB-KW.
DR InterPro; IPR001447; Arylamine_N-AcTrfase.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR PANTHER; PTHR11786; PTHR11786; 1.
DR Pfam; PF00797; Acetyltransf_2; 1.
DR SUPFAM; SSF54001; SSF54001; 1.
PE 1: Evidence at protein level;
KW Acyltransferase; Antibiotic resistance; Reference proteome; Transferase.
FT CHAIN 1..283
FT /note="Arylamine N-acetyltransferase"
FT /id="PRO_0000107919"
FT ACT_SITE 70
FT /note="Acyl-thioester intermediate"
FT /evidence="ECO:0000305|PubMed:18795795"
FT ACT_SITE 110
FT /note="Proton acceptor"
FT /evidence="ECO:0000305|PubMed:18795795"
FT ACT_SITE 127
FT /evidence="ECO:0000305|PubMed:18795795"
SQ SEQUENCE 283 AA; 31029 MW; 9C8D98E3256D088A CRC64;
MALDLTAYFD RINYRGATDP TLDVLQDLVT VHSRTIPFEN LDPLLGVPVD DLSPQALADK
LVLRRRGGYC FEHNGLMGYV LAELGYRVRR FAARVVWKLA PDAPLPPQTH TLLGVTFPGS
GGCYLVDVGF GGQTPTSPLR LETGAVQPTT HEPYRLEDRV DGFVLQAMVR DTWQTLYEFT
TQTRPQIDLK VASWYASTHP ASKFVTGLTA AVITDDARWN LSGRDLAVHR AGGTEKIRLA
DAAAVVDTLS ERFGINVADI GERGALETRI DELLARQPGA DAP
