TY - JOUR
T1 - Structure-based drug design targeting biosynthesis of isoprenoids
T2 - A crystallographic state of the art of the involved enzymes
AU - De Ruyck, Jérôme
AU - Wouters, Johan
PY - 2008/4/1
Y1 - 2008/4/1
N2 - Biosynthesis of the universal terpenoid precursors, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), from three acetyl CoA moieties through mevalonate was studied extensively in the 1950s. For several decades, the mevalonate paradigm reigned supreme and a mevalonate origin was attributed to a growing number of natural products, in many cases erroneously. Besides this biosynthetic pathway, the existence of a second one leading to IPP and DMAPP through 1-deoxy-D-xylulose 5-phosphate and 2C-methyl-D-erythricol 4-phosphate was discovered more recently in plants and some eubacteria. This pathway is widely distributed in the bacterial kingdom including major human pathogens, such as Mycobacterium tuberculosis or Helicobacter pylori and is also essential in the malaria vector Plasmodium falciparum. During the last few years, the genes, enzymes, intermediates and mechanisms of the biosynthetic route have been elucidated by a combination of methods including comparative genomics, enzymology, advanced NMR technology and crystallography. The present crystallographic review of enzymes involved in isoprenoid' biosynthesis will be useful for understanding the various catalytic mechanisms and could potentially help for structure-based drug design.
AB - Biosynthesis of the universal terpenoid precursors, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), from three acetyl CoA moieties through mevalonate was studied extensively in the 1950s. For several decades, the mevalonate paradigm reigned supreme and a mevalonate origin was attributed to a growing number of natural products, in many cases erroneously. Besides this biosynthetic pathway, the existence of a second one leading to IPP and DMAPP through 1-deoxy-D-xylulose 5-phosphate and 2C-methyl-D-erythricol 4-phosphate was discovered more recently in plants and some eubacteria. This pathway is widely distributed in the bacterial kingdom including major human pathogens, such as Mycobacterium tuberculosis or Helicobacter pylori and is also essential in the malaria vector Plasmodium falciparum. During the last few years, the genes, enzymes, intermediates and mechanisms of the biosynthetic route have been elucidated by a combination of methods including comparative genomics, enzymology, advanced NMR technology and crystallography. The present crystallographic review of enzymes involved in isoprenoid' biosynthesis will be useful for understanding the various catalytic mechanisms and could potentially help for structure-based drug design.
UR - http://www.scopus.com/inward/record.url?scp=42049122363&partnerID=8YFLogxK
U2 - 10.2174/138920308783955261
DO - 10.2174/138920308783955261
M3 - Article
C2 - 18393884
AN - SCOPUS:42049122363
SN - 1389-2037
VL - 9
SP - 117
EP - 137
JO - Current Protein and Peptide Science
JF - Current Protein and Peptide Science
IS - 2
ER -