TY - JOUR
T1 - Biosynthesis of the unique amino acid side chain of butirosin
T2 - Possible protective-group chemistry in an acyl carrier protein-mediated pathway
AU - Li, Yanyan
AU - Llewellyn, Nicholas M.
AU - Giri, Ramesh
AU - Huang, Fanglu
AU - Spencer, Jonathan B.
N1 - Funding Information:
Y.L. wishes to thank the Cambridge Overseas Trust for financial support. N.M.L. acknowledges financial support from the Marshall Scholarships. R.G. thanks the Shell Centenary Scholarship Fund for financial support. J.B.S. thanks the BBSRC for a project grant in support of this work. Grateful thanks are given to Dr. Dieter Spiteller and Dr. Tsung-Lin Li for assistance with mass spectroscopy.
PY - 2005
Y1 - 2005
N2 - Butirosins A and B are naturally occurring aminoglycoside antibiotics that have a (2S)-4-amino-2-hydroxybutyrate (AHBA) side chain. Semisynthetic addition of AHBA to clinically valuable aminoglycoside antibiotics has been shown both to improve their pharmacological properties and to prevent their deactivation by a number of aminoglycoside-modifying enzymes involved in bacterial resistance. We report here that the biosynthesis of AHBA from L-glutamate, encoded within a previously identified butirosin biosynthetic gene cluster, proceeds via intermediates tethered to a specific acyl carrier protein (ACP). Five components of the pathway have been purified and characterized, including the ACP (BtrI), an ATP-dependent ligase (BtrJ), a pyridoxal phosphate-dependent decarboxylase (BtrK), and a two-component flavin-dependent monooxygenase system (BtrO and the previously unreported BtrV). The proposed biosynthetic pathway includes a γ-glutamylation of an ACP-derived γ-aminobutyrate intermediate, possibly a rare example of protective group chemistry in biosynthesis.
AB - Butirosins A and B are naturally occurring aminoglycoside antibiotics that have a (2S)-4-amino-2-hydroxybutyrate (AHBA) side chain. Semisynthetic addition of AHBA to clinically valuable aminoglycoside antibiotics has been shown both to improve their pharmacological properties and to prevent their deactivation by a number of aminoglycoside-modifying enzymes involved in bacterial resistance. We report here that the biosynthesis of AHBA from L-glutamate, encoded within a previously identified butirosin biosynthetic gene cluster, proceeds via intermediates tethered to a specific acyl carrier protein (ACP). Five components of the pathway have been purified and characterized, including the ACP (BtrI), an ATP-dependent ligase (BtrJ), a pyridoxal phosphate-dependent decarboxylase (BtrK), and a two-component flavin-dependent monooxygenase system (BtrO and the previously unreported BtrV). The proposed biosynthetic pathway includes a γ-glutamylation of an ACP-derived γ-aminobutyrate intermediate, possibly a rare example of protective group chemistry in biosynthesis.
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U2 - 10.1016/j.chembiol.2005.04.010
DO - 10.1016/j.chembiol.2005.04.010
M3 - Article
C2 - 15975512
AN - SCOPUS:24944561674
SN - 1074-5521
VL - 12
SP - 665
EP - 675
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 6
ER -