3D-Structure and function of strictosidine synthase--the key enzyme of monoterpenoid indole alkaloid biosynthesis.
Strictosidine synthase (STR; EC 4.3.3.2) plays a key role in the biosynthesis of monoterpenoid indole alkaloids by catalyzing the Pictet-Spengler reaction between tryptamine and secologanin, leading exclusively to 3alpha-(S)-strictosidine. The structure of the native enzyme from the Indian medicinal plant Rauvolfia serpentina represents the first example of a six-bladed four-stranded beta-propeller fold from the plant kingdom. Moreover, the architecture of the enzyme-substrate and enzyme-product complexes reveals deep insight into the active centre and mechanism of the synthase highlighting the importance of Glu309 as the catalytic residue. The present review describes the 3D-structure and function of R. serpentina strictosidine synthase and provides a summary of the strictosidine synthase substrate specificity studies carried out in different organisms to date. Based on the enzyme-product complex, this paper goes on to describe a rational, structure-based redesign of the enzyme, which offers the opportunity to produce novel strictosidine derivatives which can be used to generate alkaloid libraries of the N-analogues heteroyohimbine type. Finally, alignment studies of functionally expressed strictosidine synthases are presented and the evolutionary aspects of sequence- and structure-related beta-propeller folds are discussed.
Stöckigt
Joachim
J
College of Pharmaceutical Sciences, Zijingang Campus, Zhejiang University, 310058 Hangzhou, China. stoeckig@uni-mainz.de
Barleben
Leif
L
Panjikar
Santosh
S
Loris
Elke A
EA
D019759:Carbon-Nitrogen Lyases / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D011487:Protein Conformation; D046948:Secologanin Tryptamine Alkaloids / Q000378:metabolism*; D013379:Substrate Specificity; D014748:Vinca Alkaloids / Q000737:chemistry / Q000378:metabolism
D046948:Secologanin Tryptamine Alkaloids; D014748:Vinca Alkaloids; C021093:strictosidine; D019759:Carbon-Nitrogen Lyases; C022684:strictosidine synthetase