Biosynthesis of the unique amino acid side chain of butirosin: possible protective-group chemistry in an acyl carrier protein-mediated pathway.
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 gamma-glutamylation of an ACP-derived gamma-aminobutyrate intermediate, possibly a rare example of protective group chemistry in biosynthesis.
Li
Yanyan
Y
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Llewellyn
Nicholas M
NM
Giri
Ramesh
R
Huang
Fanglu
F
Spencer
Jonathan B
JB
D000213:Acyl Carrier Protein / Q000378:metabolism*; D000215:Acylation; D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism*; D000613:Aminobutyrates / Q000737:chemistry / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism; D001407:Bacillus / Q000737:chemistry / Q000378:metabolism; D002076:Butirosin Sulfate / Q000096:biosynthesis* / Q000737:chemistry*; D018698:Glutamic Acid / Q000737:chemistry / Q000378:metabolism; D006900:Hydroxylation; D015394:Molecular Structure; D005810:Multigene Family
D000213:Acyl Carrier Protein; D000596:Amino Acids; D000613:Aminobutyrates; D000900:Anti-Bacterial Agents; C005959:2,4-diaminobutyric acid; D018698:Glutamic Acid; D002076:Butirosin Sulfate