Engineering dehydro amino acids and thioethers into peptides using lacticin 481 synthetase.
Lantibiotics are peptide antimicrobials containing the thioether-bridged amino acids lanthionine (Lan) and methyllanthionine (MeLan) and often the dehydrated residues dehydroalanine (Dha) and dehydrobutyrine (Dhb). While biologically advantageous, the incorporation of these residues into peptides is synthetically daunting, and their production in vivo is limited to peptides containing proteinogenic amino acids. The lacticin 481 synthetase LctM offers versatile control over the installation of dehydro amino acids and thioether rings into peptides. In vitro processing of semisynthetic substrates unrelated to the prelacticin 481 peptide demonstrated the broad substrate tolerance of LctM. Furthermore, a chemoenzymatic strategy was employed to generate novel thioether linkages by cyclization of peptidic substrates containing the nonproteinogenic cysteine analogs homocysteine and beta-homocysteine. These findings are promising with respect to the utility of LctM toward preparation of conformationally constrained peptide therapeutics.
Chatterjee
Champak
C
Department of Chemistry and University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801.
Patton
Gregory C
GC
Cooper
Lisa
L
Paul
Moushumi
M
van der Donk
Wilfred A
WA
D000409:Alanine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry*; D001430:Bacteriocins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003500:Cyclization; D003681:Dehydration; D004789:Enzyme Activation; D004798:Enzymes / Q000737:chemistry* / Q000378:metabolism; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D015202:Protein Engineering / Q000379:methods*; D012680:Sensitivity and Specificity; D013440:Sulfides / Q000138:chemical synthesis / Q000737:chemistry*
D000596:Amino Acids; D001430:Bacteriocins; D004798:Enzymes; C481644:LctM protein, Lactococcus lactis; D010455:Peptides; D013440:Sulfides; C082508:lacticin 481; C001520:lanthionine; D000409:Alanine