Review
Chain-length determination mechanism of isoprenyl diphosphate synthases and implications for molecular evolution

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Abstract

In the synthesis of isoprenoids, isoprenyl diphosphate synthases catalyze the consecutive condensation of isopentenyl diphosphate with allylic diphosphates to produce a variety of prenyl diphosphates with well-defined chain lengths. Site-directed mutagenesis in conjunction with X-ray crystallographic studies have identified specific amino acid residues responsible for chain-length determination. Simple combinations of these residues within a characteristic motif are not only sufficient to confer product specificities to all isoprenyl diphosphate synthases but represent structural features that reflect the enzyme family’s evolutionary course.

Section snippets

3D structures of prenyltransferases

Over the past decade, the structural genes for many types of E-isoprenyl diphosphate synthases have been cloned and characterized3. Multiple alignments of the deduced amino acid sequences revealed several conserved regions in the primary structure, including two characteristic aspartate-rich motifs, DDx2–4D and DDxxD (Fig. 2a)1, 4. Site-directed mutational analysis of amino acids in the highly conserved regions demonstrated their crucial roles in substrate binding and catalytic activity, which

Conservation between E- and Z-isoprenyl diphosphate synthases?

Recently, Shimizu et al. cloned the gene for undecaprenyl diphosphate synthase (UPP), thereby providing the first identification and purification of a Z-isoprenyl diphosphate synthase2. The primary structure of UPP synthase is completely different from those of E-isoprenyl diphosphate synthases and, even though a DDxxD motif-like structure is present in the enzyme, it seems premature to designate it as an equally crucial region corresponding to that of the E-isoprenyl diphosphate synthases. It

Mechanism of chain-length determination by E-isoprenyl diphosphate synthases

Some of the most interesting research into the catalytic mechanism of prenyltransferases is aimed at understanding the mechanism by which individual enzymes recognize chain lengths of substrates or products, or both. As mentioned previously, despite identical condensation mechanisms, these enzymes rarely catalyze the formation of products greater than a pre-determined length specific to each prenyltransferase. For example, FPP synthase produces a C15 compound and hardly any C20. A different

Creating evolutionary diversity from changes in CLD composition

The idea that E-isoprenyl diphosphate synthases were produced by divergent evolution was first proposed in 1994 by Chen et al., who compared amino acid sequences of 13 distinct enzymes in the family that were available at the time1. One of the main conclusions from the study was that Methanobacterium thermoautotrophicum GGPP synthase, the bifunctional archaeal enzyme that produces FPP as an intermediate23, is an ancient ‘pre-enzyme’ and that the earliest branch in isoprenyl diphosphate synthase

Concluding remarks

This review presents evidence for a relationship between the structural requirements for product specificities and the phylogenetic tree of E-isoprenyl diphosphate synthases and suggests a possible evolutionary course with the assumption that archaeal GGPP synthase is closest in time to the common ancestor. However, this might not be a valid assumption to make. In the future, more precise evolutionary analyses need to be integrated, by using a larger number of samples with phylogenetic data

Acknowledgements

S-i. Ohnuma thanks K. Ogura, T. Koyama, T. Nishino and H. Sagami for support and encouragement. S-i. Ohnuma also thanks members of the Nishino laboratory.

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