The Enzyme Database

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EC 1.1.1.355     
Accepted name: 2′-dehydrokanamycin reductase
Reaction: kanamycin A + NADP+ = 2′-dehydrokanamycin A + NADPH + H+
For diagram of kanamycin A biosynthesis, click here
Glossary: kanamycin A = (1S,2R,3R,4S,6R)-4,6-diamino-3-(6-amino-6-deoxy-α-D-glucopyranosyloxy)-2-hydroxycyclohexyl 3-amino-3-deoxy-α-D-glucopyranoside
2′-dehydrokanamycin A = (1S,2R,3R,4S,6R)-4,6-diamino-3-[(6-amino-6-deoxy-α-D-arabino-hexopyranosyl-2-ulose)oxy]-2-hydroxycyclohexyl 3-amino-3-deoxy-α-D-glucopyranoside
Other name(s): kanK (gene name, ambiguous)
Systematic name: kanamycin A:NADP+ oxidoreductase
Comments: Found in the bacterium Streptomyces kanamyceticus where it is involved in the conversion of kanamycin B to kanamycin A.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Sucipto, H., Kudo, F. and Eguchi, T. The last step of kanamycin biosynthesis: unique deamination reaction catalyzed by the α-ketoglutarate-dependent nonheme iron dioxygenase KanJ and the NADPH-dependent reductase KanK. Angew. Chem. Int. Ed. Engl. 51 (2012) 3428–3431. [DOI] [PMID: 22374809]
[EC 1.1.1.355 created 2013]
 
 
EC 1.14.11.37     
Accepted name: kanamycin B dioxygenase
Reaction: kanamycin B + 2-oxoglutarate + O2 = 2′-dehydrokanamycin A + succinate + NH3 + CO2
For diagram of kanamycin A biosynthesis, click here
Other name(s): kanJ (gene name)
Systematic name: kanamycin-B,2-oxoglutarate:oxygen oxidoreductase (deaminating, 2′-hydroxylating)
Comments: Requires Fe2+ and ascorbate. Found in the bacterium Streptomyces kanamyceticus where it is involved in the conversion of the aminoglycoside antibiotic kanamycin B to kanamycin A.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Sucipto, H., Kudo, F. and Eguchi, T. The last step of kanamycin biosynthesis: unique deamination reaction catalyzed by the α-ketoglutarate-dependent nonheme iron dioxygenase KanJ and the NADPH-dependent reductase KanK. Angew. Chem. Int. Ed. Engl. 51 (2012) 3428–3431. [DOI] [PMID: 22374809]
[EC 1.14.11.37 created 2013, modified 2013]
 
 
EC 2.1.3.13      
Deleted entry: ATP carbamoyltransferase. The enzyme has been replaced by EC 6.1.2.2, nebramycin 5′ synthase.
[EC 2.1.3.13 created 2013, deleted 2014]
 
 
EC 2.1.3.14      
Deleted entry: tobramycin carbamoyltransferase. The enzyme has been replaced by EC 6.1.2.2, nebramycin 5′ synthase
[EC 2.1.3.14 created 2013, deleted 2014]
 
 
EC 2.3.1.82     
Accepted name: aminoglycoside 6′-N-acetyltransferase
Reaction: acetyl-CoA + kanamycin-B = CoA + N6′-acetylkanamycin-B
Glossary: kanamycin
Other name(s): aminoglycoside N6′-acetyltransferase; aminoglycoside-6′-acetyltransferase; aminoglycoside-6-N-acetyltransferase; kanamycin acetyltransferase
Systematic name: acetyl-CoA:kanamycin-B N6′-acetyltransferase
Comments: The antibiotics kanamycin A, kanamycin B, neomycin, gentamicin C1a, gentamicin C2 and sisomicin are substrates. The antibiotic tobramycin, but not paromomycin, can also act as acceptor. The 6-amino group of the purpurosamine ring is acetylated.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 56467-65-3
References:
1.  le Goffic, F. and Martel, A. La résistance aux aminosides provoquée par une isoenzyme la kanamycine acétyltransférase. Biochimie 56 (1974) 893–897. [DOI] [PMID: 4614862]
2.  Benveniste, R. and Davies, J.E. Enzymatic acetylation of aminoglycoside antibiotics by Escherichia coli carrying an R factor. Biochemistry 10 (1971) 1787–1796. [PMID: 4935296]
3.  Dowding, J.E. Mechanisms of gentamicin resistance in Staphylococcus aureus. Antimicrob. Agents Chemother. 11 (1977) 47–50. [PMID: 836013]
[EC 2.3.1.82 created 1976 as EC 2.3.1.55, transferred 1999 to EC 2.3.1.82, modified 1999, modified 2015]
 
 
EC 2.4.1.301     
Accepted name: 2′-deamino-2′-hydroxyneamine 1-α-D-kanosaminyltransferase
Reaction: (1) UDP-α-D-kanosamine + 2′-deamino-2′-hydroxyneamine = UDP + kanamycin A
(2) UDP-α-D-kanosamine + neamine = UDP + kanamycin B
(3) UDP-α-D-kanosamine + paromamine = UDP + kanamycin C
(4) UDP-α-D-kanosamine + 2′-deamino-2′-hydroxyparomamine = UDP + kanamycin X
For diagram of kanamycin A biosynthesis, click here
Glossary: neamine = (1R,2R,3S,4R,6S)-4,6-diamino-2,3-dihydroxycyclohexyl 2,6-diamino-2,6-dideoxy-α-D-glucopyranoside
paromamine = (1R,2R,3S,4R,6S)-4,6-diamino-2,3-dihydroxycyclohexyl 2-amino-2-deoxy-α-D-glucopyranoside
UDP-α-D-kanosamine = uridine 5′-[3-(3-amino-3-deoxy-α-D-glucopyranosyl) diphosphate]
kanamycin A = (1S,2R,3R,4S,6R)-4,6-diamino-3-(6-amino-6-deoxy-α-D-glucopyranosyloxy)-2-hydroxycyclohexyl 3-amino-3-deoxy-α-D-glucopyranoside
kanamycin B = (1R,2S,3S,4R,6S)-4,6-diamino-3-(3-amino-3-deoxy-α-D-glucopyranosyloxy)-2-hydroxycyclohexyl 2,6-diamino-2,6-dideoxy-α-D-glucopyranoside
kanamycin C = (1R,2S,3S,4R,6S)-4,6-diamino-3-(3-amino-3-deoxy-α-D-glucopyranosyloxy)-2-hydroxycyclohexyl 2-amino-2-deoxy-α-D-glucopyranoside
kanamycin X = (1S,2R,3R,4S,6R)-4,6-diamino-3-(α-D-glucopyranosyloxy)-2-hydroxycyclohexyl 3-amino-3-deoxy-α-D-glucopyranoside
Other name(s): kanE (gene name); kanM2 (gene name)
Systematic name: UDP-α-D-kanosamine:2′-deamino-2′-hydroxyneamine 1-α-D-kanosaminyltransferase
Comments: Involved in the biosynthetic pathway of kanamycins. The enzyme characterized from the bacterium Streptomyces kanamyceticus can also accept UDP-α-D-glucose with lower efficiency [2].
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Kudo, F., Sucipto, H. and Eguchi, T. Enzymatic activity of a glycosyltransferase KanM2 encoded in the kanamycin biosynthetic gene cluster. J. Antibiot. (Tokyo) 62 (2009) 707–710. [DOI] [PMID: 19911031]
2.  Park, J.W., Park, S.R., Nepal, K.K., Han, A.R., Ban, Y.H., Yoo, Y.J., Kim, E.J., Kim, E.M., Kim, D., Sohng, J.K. and Yoon, Y.J. Discovery of parallel pathways of kanamycin biosynthesis allows antibiotic manipulation. Nat. Chem. Biol. 7 (2011) 843–852. [DOI] [PMID: 21983602]
[EC 2.4.1.301 created 2013]
 
 
EC 2.6.1.93     
Accepted name: neamine transaminase
Reaction: neamine + 2-oxoglutarate = 6′-dehydroparomamine + L-glutamate
For diagram of neamine and ribostamycin biosynthesis, click here
Other name(s): glutamate—6′-dehydroparomamine aminotransferase; btrB (gene name); neoN (gene name); kacL (gene name)
Systematic name: neamine:2-oxoglutarate aminotransferase
Comments: The reaction occurs in vivo in the opposite direction. Involved in the biosynthetic pathways of several clinically important aminocyclitol antibiotics, including kanamycin B, butirosin, neomycin and ribostamycin. Works in combination with EC 1.1.3.43, paromamine 6-oxidase, to replace the 6′-hydroxy group of paromamine with an amino group. The enzyme from the bacterium Streptomyces kanamyceticus can also catalyse EC 2.6.1.94, 2′-deamino-2′-hydroxyneamine transaminase, which leads to production of kanamycin A [3]. The enzyme from the bacterium Streptomyces fradiae can also catalyse EC 2.6.1.95, leading to production of neomycin C [2].
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Huang, F., Spiteller, D., Koorbanally, N.A., Li, Y., Llewellyn, N.M. and Spencer, J.B. Elaboration of neosamine rings in the biosynthesis of neomycin and butirosin. ChemBioChem 8 (2007) 283–288. [DOI] [PMID: 17206729]
2.  Clausnitzer, D., Piepersberg, W. and Wehmeier, U.F. The oxidoreductases LivQ and NeoQ are responsible for the different 6′-modifications in the aminoglycosides lividomycin and neomycin. J. Appl. Microbiol. 111 (2011) 642–651. [DOI] [PMID: 21689223]
3.  Park, J.W., Park, S.R., Nepal, K.K., Han, A.R., Ban, Y.H., Yoo, Y.J., Kim, E.J., Kim, E.M., Kim, D., Sohng, J.K. and Yoon, Y.J. Discovery of parallel pathways of kanamycin biosynthesis allows antibiotic manipulation. Nat. Chem. Biol. 7 (2011) 843–852. [DOI] [PMID: 21983602]
[EC 2.6.1.93 created 2012]
 
 
EC 2.6.1.94     
Accepted name: 2′-deamino-2′-hydroxyneamine transaminase
Reaction: 2′-deamino-2′-hydroxyneamine + 2-oxoglutarate = 2′-deamino-2′-hydroxy-6′-dehydroparomamine + L-glutamate
Other name(s): kacL (gene name)
Systematic name: 2′-deamino-2′-hydroxyneamine:2-oxoglutarate aminotransferase
Comments: The reaction occurs in vivo in the opposite direction. Involved in the biosynthetic pathway of kanamycin A and kanamycin D. The enzyme, characterized from the bacterium Streptomyces kanamyceticus, can also catalyse EC 2.6.1.93, neamine transaminase.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Park, J.W., Park, S.R., Nepal, K.K., Han, A.R., Ban, Y.H., Yoo, Y.J., Kim, E.J., Kim, E.M., Kim, D., Sohng, J.K. and Yoon, Y.J. Discovery of parallel pathways of kanamycin biosynthesis allows antibiotic manipulation. Nat. Chem. Biol. 7 (2011) 843–852. [DOI] [PMID: 21983602]
[EC 2.6.1.94 created 2012]
 
 
EC 2.7.1.190     
Accepted name: aminoglycoside 2′′-phosphotransferase
Reaction: GTP + gentamicin = GDP + gentamicin 2′′-phosphate
Other name(s): aphD (gene name); APH(2′′); aminoglycoside (2′′) kinase; gentamicin kinase (ambiguous); gentamicin phosphotransferase (ambiguous)
Systematic name: GTP:gentamicin 2′′-O-phosphotransferase
Comments: Requires Mg2+. This bacterial enzyme phosphorylates many 4,6-disubstituted aminoglycoside antibiotics that have a hydroxyl group at position 2′′, including kanamycin A, kanamycin B, tobramycin, dibekacin, arbekacin, amikacin, gentamicin C, sisomicin and netilmicin. In most, but not all, cases the phosphorylation confers resistance against the antibiotic. Some forms of the enzyme use ATP as a phosphate donor in appreciable amount. The enzyme is often found as a bifunctional enzyme that also catalyses 6′-aminoglycoside N-acetyltransferase activity. The bifunctional enzyme is the most clinically important aminoglycoside-modifying enzyme in Gram-positive bacteria, responsible for high-level resistance in both Enterococci and Staphylococci.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Ferretti, J.J., Gilmore, K.S. and Courvalin, P. Nucleotide sequence analysis of the gene specifying the bifunctional 6′-aminoglycoside acetyltransferase 2"-aminoglycoside phosphotransferase enzyme in Streptococcus faecalis and identification and cloning of gene regions specifying the two activities. J. Bacteriol. 167 (1986) 631–638. [DOI] [PMID: 3015884]
2.  Frase, H., Toth, M. and Vakulenko, S.B. Revisiting the nucleotide and aminoglycoside substrate specificity of the bifunctional aminoglycoside acetyltransferase(6′)-Ie/aminoglycoside phosphotransferase(2′′)-Ia enzyme. J. Biol. Chem. 287 (2012) 43262–43269. [DOI] [PMID: 23115238]
[EC 2.7.1.190 created 2015]
 
 
EC 6.1.2.2     
Accepted name: nebramycin 5′ synthase
Reaction: (1) tobramycin + carbamoyl phosphate + ATP + H2O = nebramycin 5′ + AMP + diphosphate + phosphate (overall reaction)
(1a) carbamoyl phosphate + ATP + H2O = diphosphate + O-carbamoyladenylate + phosphate
(1b) O-carbamoyladenylate + tobramycin = AMP + nebramycin 5′
(2) kanamycin A + carbamoyl phosphate + ATP + H2O = 6′′-O-carbamoylkanamycin A + AMP + diphosphate + phosphate (overall reaction)
(2a) carbamoyl phosphate + ATP + H2O = diphosphate + O-carbamoyladenylate + phosphate
(2b) O-carbamoyladenylate + kanamycin A = AMP + 6′′-O-carbamoylkanamycin A
For diagram of kanamycin A biosynthesis, click here
Glossary: tobramycin = (1S,2S,3R,4S,6R)-4,6-diamino-3-(2,6-diamino-2,3,6-trideoxy-α-D-ribo-hexopyranosyloxy)-2-hydroxycyclohexyl 3-amino-3-deoxy-α-D-glucopyranoside
nebramycin 5′ = (1S,2S,3R,4S,6R)-4,6-diamino-3-[(2,6-diamino-2,3,6-trideoxy-α-D-ribo-hexopyranosyl)oxy]-2-hydroxycyclohexyl 3-amino-6-O-carbamoyl-3-deoxy-α-D-glucopyranoside
kanamycin A = (1S,2R,3R,4S,6R)-4,6-diamino-3-(6-amino-6-deoxy--D-glucopyranosyloxy)-2-hydroxycyclohexyl 3-amino-3-deoxy--D-glucopyranoside
6′′-O-carbamoylkanamycin A = (1S,2R,3R,4S,6R)-4,6-diamino-3-[(6-amino-6-deoxy-α-D-glucopyranosyl)oxy]-2-hydroxycyclohexyl 3-amino-6-O-carbamoyl-3-deoxy-α-D-glucopyranoside
Other name(s): tobramycin carbamoyltransferase; TobZ
Systematic name: tobramycin:carbamoyl phosphate ligase (AMP,phosphate-forming)
Comments: Requires Fe(III). The enzyme from the bacterium Streptoalloteichus tenebrarius catalyses the activation of carbamoyl phosphate to O-carbamoyladenylate and the subsequent carbamoylation of kanamycin and tobramycin.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Parthier, C., Gorlich, S., Jaenecke, F., Breithaupt, C., Brauer, U., Fandrich, U., Clausnitzer, D., Wehmeier, U.F., Bottcher, C., Scheel, D. and Stubbs, M.T. The O-carbamoyltransferase TobZ catalyzes an ancient enzymatic reaction. Angew. Chem. Int. Ed. Engl. 51 (2012) 4046–4052. [DOI] [PMID: 22383337]
[EC 6.1.2.2 created 2014]
 
 


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