Inhibitors of polyhydroxyalkanoate (PHA) synthases: synthesis, molecular docking, and implications.
Polyhydroxyalkanoate (PHA) synthases (PhaCs) catalyze the formation of biodegradable PHAs that are considered to be ideal alternatives to non-biodegradable synthetic plastics. However, study of PhaCs has been challenging because the rate of PHA chain elongation is much faster than that of initiation. This difficulty, along with lack of a crystal structure, has become the main hurdle to understanding and engineering PhaCs for economical PHA production. Here we report the synthesis of two carbadethia CoA analogues--sT-CH2-CoA (26 a) and sTet-CH2-CoA (26 b)--as well as sT-aldehyde (saturated trimer aldehyde, 29), as new PhaC inhibitors. Study of these analogues with PhaECAv revealed that 26 a/b and 29 are competitive and mixed inhibitors, respectively. Both the CoA moiety and extension of PHA chain will increase binding affinity; this is consistent with our docking study. Estimation of the Kic values of 26 a and 26 b predicts that a CoA analogue incorporating an octameric hydroxybutanoate (HB) chain might facilitate the formation of a kinetically well-behaved synthase.
Department of Chemistry, Kansas State Univerity, Manhattan, KS 66506 (USA).
Wei
W
Zhang
Department of Chemistry, Kansas State Univerity, Manhattan, KS 66506 (USA).
Chao
C
Chen
Department of Chemistry, Kansas State Univerity, Manhattan, KS 66506 (USA).
Ruikai
R
Cao
Department of Chemistry, Kansas State Univerity, Manhattan, KS 66506 (USA).
Leila
L
Maurmann
Department of Chemistry, Kansas State Univerity, Manhattan, KS 66506 (USA).
Ping
P
Li
D000217:Acyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D000447:Aldehydes / Q000138:chemical synthesis / Q000737:chemistry*; D000818:Animals; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D055162:Biocatalysis; D001673:Biodegradation, Environmental; D003065:Coenzyme A / Q000138:chemical synthesis / Q000737:chemistry*; D020118:Cupriavidus necator / Q000737:chemistry / Q000201:enzymology; D004285:Dogs; D057075:Enzyme Assays; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D004950:Esterases / Q000737:chemistry; D007700:Kinetics; D008049:Lipase / Q000737:chemistry; D062105:Molecular Docking Simulation; D010204:Pantetheine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D054813:Polyhydroxyalkanoates / Q000737:chemistry* / Q000378:metabolism; D040681:Structural Homology, Protein; D013379:Substrate Specificity; D048229:Sulfolobus solfataricus / Q000737:chemistry / Q000201:enzymology
D000217:Acyltransferases; D000447:Aldehydes; D001426:Bacterial Proteins; D003065:Coenzyme A; D004791:Enzyme Inhibitors; D004950:Esterases; D008049:Lipase; D010204:Pantetheine; D054813:Polyhydroxyalkanoates; C077225:poly(3-hydroxyalkanoic acid) synthase; C485982:LIPF protein, human; C003129:4'-phosphopantetheine
PHA synthases; chemoenzymatic approach; inhibitors; molecular docking; synthesis design