Enzymatic synthesis of a selective inhibitor for alpha-glucosidases: alpha-acarviosinyl-(1-->9)-3-alpha-D-glucopyranosylpropen.
Here, we describe the enzymatic synthesis of novel inhibitors using acarviosine-glucose as a donor and 3-alpha-D-glucopyranosylpropen (alphaGP) as an acceptor. Maltogenic amylase from Thermus sp. (ThMA) catalyzed the transglycosylation of the acarviosine moiety to alphaGP. The two major reaction products were isolated using chromatographies. Structural analyses revealed that acarviosine was transferred to either C-7 or C-9 of the alphaGP, which correspond to C-4 and C-6 of glucose. Both inhibited rat intestine alpha-glucosidase competitively but displayed a mixed-type inhibition mode against human pancreatic alpha-amylase. The alpha-acarviosinyl-(1-->7)-3-alpha-D-glucopyranosylpropen showed weaker inhibition potency than acarbose against both alpha-glycosidases. In contrast, the alpha-acarviosinyl-(1-->9)-3-alpha-D-glucopyranosylpropen exhibited a 3.0-fold improved inhibition potency against rat intestine alpha-glucosidase with 0.3-fold inhibition potency against human pancreatic alpha-amylase relative to acarbose. In conclusion, alpha-acarviosinyl-(1-->9)-3-alpha-D-glucopyranosylpropen is a novel alpha-glucosidase-selective inhibitor with 10-fold enhanced selectivity toward alpha-glucosidase over alpha-amylase relative to acarbose, and it could be applied as a potent hypoglycemic agent.
Lee
Young-Su
YS
Center for Agricultural Biomaterials and School of Agriculture and Biotechnology, Seoul National University, Seoul 151-921, Korea.
Lee
Myoung-Hee
MH
Lee
Hee-Seob
HS
Lee
Seung-Jae
SJ
Kim
Young-Wan
YW
Zhang
Ran
R
Withers
Stephen G
SG
Kim
Kwan Soo
KS
Lee
Sung-Joon
SJ
Park
Kwan-Hwa
KH
D020909:Acarbose / Q000031:analogs & derivatives / Q000378:metabolism; D000498:Allyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000201:enzymology; D004187:Disaccharides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D065089:Glycoside Hydrolase Inhibitors; D006801:Humans; D007700:Kinetics; D051381:Rats; D013824:Thermus / Q000201:enzymology; D000516:alpha-Amylases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000520:alpha-Glucosidases / Q000737:chemistry / Q000378:metabolism
D000498:Allyl Compounds; D004187:Disaccharides; D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; C531014:acarviosinyl-(1-9)-3-glucopyranosylpropene; D000516:alpha-Amylases; D000520:alpha-Glucosidases; D020909:Acarbose