This document summarizes the non-mevalonate pathway for isoprenoid biosynthesis. It notes that plants, protozoa like malaria parasites, and most bacteria use this alternative pathway located in their plastids to produce isoprenoids. The pathway converts pyruvate and glyceraldehyde 3-phosphate into isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) through a series of enzymatic reactions. Inhibitors of 1-deoxy-D-xylulose 5-phosphate reductoisomerase, a key enzyme in this pathway, like fosmidomycin and its derivative FR-900098, show potential as new

1. BIOSYNTHESISOF ISOPRENOIDS

3.  In contrast to the classical mevalonate
pathway of isoprenoid
biosynthesis, plants and protozoa such
as malaria parasites have the ability to
produce their isoprenoids (terpenoids) using
an alternative pathway, the non-
mevalonate pathway, which occurs in their
plastids.

4.  In addition, most bacteria including
important pathogens such as Mycobacterium
tuberculosis synthesize IPP and DMAPP via
the non-mevalonate pathway.

6. Reactants Enzyme Product
Pyruvate andglyceraldehyde 3-
phosphate
DOXP synthase (Dxs)
1-Deoxy-D-xylulose 5-
phosphate (DOXP)
DOXP DOXP reductase (Dxr, IspC)
2-C-methylerythritol 4-
phosphate (MEP)
MEP
2-C-methyl-D-erythriol 4-
phosphate
cytidyltransferase (YgbP, IspD)
4-diphosphocytidyl-2-C-
methylerythritol(CDP-ME)
CDP-ME
4-diphosphocytidyl-2-C-methyl-D-
erythritol kinase (YchB, IspE)
4-diphosphocytidyl-2-C-methyl-D-
erythritol 2-phosphate (CDP-MEP)
CDP-MEP
2-C-methyl-D-erythritol 2,4-
cyclodiphosphate synthase (YgbB,
IspF)
2-C-methyl-D-erythritol 2,4-
cyclopyrophosphate (MEcPP)
MEcPP HMB-PP synthase (GcpE, IspG)
(E)-4-Hydroxy-3-methyl-but-2-enyl
pyrophosphate (HMB-PP)
HMB-PP HMB-PP reductase (LytB, IspH) IPP and DMAPP

8.  Fosmidomycin and its derivative, FR-
900098, specifically inhibit DOXP
reductoisomerase, a key enzyme in the non-
mevalonate pathway, and therefore
represent attractive candidates as antibiotics
or antimalarial drugs.

9.  DOXP is also a precursor in the synthesis of
thiamin (Vitamin B1) and Pyridoxal (Vitamin
B6)