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Review
. 2009 Oct;13(4):492-8.
doi: 10.1016/j.cbpa.2009.06.019. Epub 2009 Jul 23.

Mechanistic advances in plant natural product enzymes

Aimee R Usera  1 , Sarah E O'Connor
Affiliations
Review

Mechanistic advances in plant natural product enzymes

Aimee R Usera et al. Curr Opin Chem Biol. 2009 Oct.

Abstract

The biosynthetic pathways of plant natural products offer an abundance of knowledge to scientists in many fields. Synthetic chemists can be inspired by the synthetic strategies that nature uses to construct these compounds. Chemical and biological engineers are working to reprogram these biosynthetic pathways to more efficiently produce valuable products. Finally, biochemists and enzymologists are interested in the detailed mechanisms of the complex transformations involved in the construction of these natural products. Study of biosynthetic enzymes and pathways therefore has a wide-ranging impact. In recent years, many plant biosynthetic pathways have been characterized, particularly the pathways that are responsible for alkaloid biosynthesis. Here we highlight recently studied alkaloid biosynthetic enzymes that catalyze production of numerous complex medicinal compounds, as well as the specifier proteins in glucosinosolate biosynthesis, whose structure and mechanism of action are just beginning to be unraveled.

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Figures

Figure 1
Figure 1
Enzymes from natural product biosynthetic pathways convert simple starting materials from primary metabolism into complex natural products. Representative pharmaceutically important compounds derived from plants are shown.
Figure 2
Figure 2
Enzymes that catalyze the Pictet-Spengler reaction are shown. A. Strictosidine synthase catalyzes the condensation of secologanin and trypamine to form an iminium species. The nucleophilic indole then attacks the iminium, and deprotonation leads to the strictosidine product. Computational studies suggest that pathway A is favored. Glu309 is believed to be responsible for all acid-base catalysis. B. Norcoclaurine synthase catalyzes iminium formation between dopamine and 4-HPAA (4-hydroxyphenylacetaldehyde). Lys122 is proposed to enhance the electrophilicity of the aldehyde so that iminium formation is facilitated. The C-2 hydroxyl group may be deprotonated prior to cyclization of the aromatic group onto the iminium. However, it is not clear which protein residues assist in this step. Glu110 may be involved in deprotonation of the final reaction intermediate to lead to formation of the product, (S)-norcoclaurine.
Figure 3
Figure 3
The berberine bridge enzyme catalyzes carbon-carbon bond formation between the N-methyl group and the C-2′ carbon of (S)-reticuline. Deprotonation of the C-3′ hydroxyl group is critical for enhancing the nucleophilicity of the C-2′ carbon for attack on the N-methyl group. As the carbon-carbon bond is formed, a hydride from the N-methyl group is transferred to the flavin. A base, not yet definitively identified, deprotonates the reaction intermediate to yield (S)-scoulerine.
Figure 4
Figure 4
Glucoinosolates are deglycosylated by myrosinase, and the resulting aglycone product rearranges to form isothiocyanates. However, when specifier proteins such as epithiospecifier protein (ESP) and thiocyanate-forming protein (TFP) the reaction pathway changes to yield epithionitriles, nitriles and thicyanates. The mechanistic details of these specifier proteins remain to be elucidated.
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