Bioorganic chemistry. A natural reunion of the physical and life sciences

Abstract

Organic substances were conceived as those found in living organisms. Although the definition was soon broadened to include all carbon-containing compounds, naturally occurring molecules have always held a special fascination for organic chemists. From these beginnings, molecules from nature were indespensible tools as generations of organic chemists developed new techniques for determining structures, analyzed the mechanisms of reactions, explored the effects conformation and stereochemistry on reactions, and found challenging new targets to synthesize. Only recently have organic chemists harnessed the powerful techniques of organic chemistry to study the functions of organic molecules in their biological hosts, the enzymes that synthesize molecules and the complex processes that occur in a cell. In this Perspective, I present a personal account of my entree into bioorganic chemistry as a physical organic chemist and subsequent work to understand the chemical mechanisms of enzyme-catalyzed reactions, to develop techniques to identify and assign hydrogen bonds in tRNAs through NMR studies with isotopically labeled molecules, and to study how structure determines function in biosynthetic enzymes with proteins obtained by genetic engineering.

Figure 1

Chiral centers in squalene synthesized from labeled (R)-mevalonic acid.

Figure 2

Hammett plot of relative rates for solvolysis of allylic methoxymethanesulfonates versus chain elongation of 3-substituted geranyl diphosphates by farnesyl diphosphate synthase, slope = 0.9.

Figure 3

Sites of incorporation of labeled uracil into uridine and modified uridine bases in tRNA^fMet.

Figure 4

¹H NMR spectra of ¹⁵N labeled and unlabeled E. coli tRNA^fMet.

Figure 5

¹H NMR spectrum for tRNA^fMet (part a). Difference decoupled spectrum with irradiation at 36.487132 MHz (part b) and 36.486450 MHz (part b).

Figure 6

¹H-¹⁵N multiquantum 2D spectrum of E. coli tRNA^fMet.

Figure 7

Isoprenoid carbon skeletons from joining two units (condensation) and from rearrangements of the c1′-2-3 skeleton.

Figure 8

X-ray structure of farnesyl diphosphate synthase showing the six helicies containing highly conserved sequences that form the active site.

Figure 9

Crystal structures of farnesyl diphosphate synthase (E-selective) and undecaprenyl diphosphate synthase (Z)-selective.

Figure 10

Farnesyl diphosphate synthase (FPP), chrysanthemyl diphosphate synthase (CPP), and chimeras constructed by replacing FPP sequence with CPP sequence starting at the N-terminus of FPP. The proteins are named according the number of amino acids in farnesyl diphosphate synthase that have been replaced by the corresponding amino acids from chrysanthemyl diphosphate synthase.

Scheme 1

Reactions catalyzed by squalene synthase.

Scheme 2

Mechanism for the rearrangement of presqualene diphosphate to squalene.

Scheme 3

Products from solvolysis of N-methyl-4-chrysanthemyloxypyridinium iodide and naturally occurring irregular monoterpenes with related carbon skeletons (blue).

Scheme 4

Synthesis of farnesyl diphosphate from dimethylallyl diphosphate

Scheme 5

Stereochemistry for chain elongation by farnesyl diphosphate synthase. X-Group and allylic carbocation alkylation mechanisms.

Scheme 6

Prenyl transfer reaction with nucleophilic moieties shown in green and dissociative and associative mechanisms with allylic electrophiles shown in red.

Scheme 7

pK_a’s for 1^st and 2^nd protonations of uracil.

Scheme 8

Solvolysis of presqualene diphosphate by squalene synthase (R = C₁₁H₁₉).

Scheme 9

Proposed role for chrysanthemyl diphosphate synthase in biosynthesis of chrysanthemol and chrysanthemic acid.

Scheme 10

Products synthesized by farnesyl diphosphate, chrysanthemyl diphosphate, and chimeras of the two enzymes when incubated with isopentenyl diphosphate and dimethylallyl diphosphate. The carbon skeletons in these compounds represent the four structures formed in nature by combination of two smaller isoprenoid units.

Scheme 11

A dissociative electrophilic alkylation mechanism for biosynthesis of c1′-2-3, 1′-2, and c2-1′-2-′3 isoprenoid compounds.

Scheme 12

Regio- and chemoselective attachment of proteins to silica surfaces.