Current Organic Chemistry - Volume 5, Issue 2, 2001

Catalytic mechanism of 3-deoxy-D-manno-2-octulosonate-8-phosphate (KDO8P) synthase (EC 4.1.2.16), an enzyme involved in the biosynthesis of lipopolysaccharides of Gram-negative bacteria, remains a fascinating subject for both bioorganic and medicinal researches. The enzyme catalyzes an aldol-type condensation of D-arabinose 5-phosphate with phosphoenolpyruvate to produce the unusual eight-carbon saccharide KDO8P and inorganic phosphate. The structure and mechanism of KDO8P synthase have actively studied during last decade as this enzyme represents an important target for antibiotic therapy. This review summarizes the most mechanistically relevant information reported to date, with special emphases on the synthesis and evaluation of a number of analogues of substrates, product and proposed intermediates of the KDO8P-synthase- catalyzed reaction. The results introduced here illustrate the value of organic synthesis to characterize enzymatic reaction. Mechanistic postulates have pointed the way to the design of potent inhibitors, and these in turn have provided insight into details of the reaction, as well as useful structural models for elusive intermediates.

A recent estimate suggests roughly 70percent of current lead compounds in modern drug discovery derive directly from the natural products, many of which are glycosylated bacterial metabolites. Thus, bacterial glycosyltransferases and their corresponding sugar substrates contribute significantly to the diversity of pharmaceutically important metabolites. This review summarizes (i) the role that carbohydrates contribute to biologically active bacterial metabolites, (ii ) a sequence homology classification of known glycosyltransferases from these systems and (iii) the potential impact pathway engineering and combinatorial biocatalysis may have on increasing carbohydrate-ligand diversity. While the number of glycosylated bacterial metabolites is vast, this review limits itself to glycosides with considerable published information pertaining to biological activity and biosynthesis.

Sugar nucleotides serve as the activated forms of carbohydrates that are used in a wide range of biosynthetic pathways. Instead of building up the sugar nucleotide from the free sugar itself, nature often chooses to modify the donor portion of a pre-existing sugar nucleotide in a biosynthetically efficient manner. In doing so a rich variety of catalytic strategies are employed and this review focuses on recent mechanistic and structural studies of the sugar nucleotide-modifying enzymes. The review is organized around the types of reactions catalyzed and contains the following sections Epimerases/Mutases/Decarboxylases, Eliminations and Substitutions, Oxidation and Reduction, and Substitutions on the Periphery of Sugar Nucleotides.

Aminoglycoside antibiotics remain to the present date as important chemotherapeutic agents, which have been in clinical use for over 50 years. These antibiotics are multifunctional and have been challenging targets for synthetic chemists. Recent developments in understanding of the mechanism of action and of resistance to these agents have stimulated additional interest in these antibiotics. The present report discussed these efforts in the field for the past few years.

The first total synthesis and development of a variety of bioactive compounds have been accomplished mainly by using carbohydrates, if any, as chiral sources. The target molecules are macrolide antibiotics, aminoglycoside antibiotics, antifungal antibiotics, antitumor antibiotics, a side-chain of b-lactam antibiotics, enzyme inhibitors including glycosidase inhibitors, central nervous system - affecting products, nonsteroidal progesterone receptor ligands, mussel-attachment inhibitors and so on.

Spiroacetals, cryptic ketodiols showing a hydroxyl group at both sides of a carbonyl whithin reachable distances are very widespread in nature. A group of 30 different structures, not including stereoisomers, represent volatile, less polar constituents of insect secretions.Five different systems were identified 1,6-dioxaspiro[ 4.4]nonanes, 1,6-dioxaspiro[4.5]decanes, 1,6-dioxaspiro[4.6]undecanes, 1,7-dioxaspiro[5.5]undecanes, and 1,7-dioxaspiro[5.6]dodecanes. Some spiroacetals are insect pheromones (2S,5R)-2-ethyl-1,6-dioxaspiro[4.4]nonane, chalcogran, 1, is a key component of the male produced aggregation pheromone of the spruce bark beetle, Pityogenes chalcographus. In contrast, (5S,7S)-7-methyl-1,6-dioxaspiro[4.5]decane, 2, conophthorin, acts as a repellent or spacer in several bark beetles. Racemic 1,7-dioxaspiro[5.5]undecane, olean, 5, is the female produced sex pheromone of the olive fly, Bactrocera (Dacus) oleae. The most widespread spiroacetal is 2,8-dimethyl-1,7-dioxaspiro[ 5.5]undecane, 8. It often forms a mixture of (E,E)- and (E,Z)-isomers, the (E,E)-isomer showing (2S,6R,8S)-configuration. In the solitary bee, Andrena wilkella, it serves as an aggregation pheromone. Present knowledge on structures and distribution of volatile spiroacetals is comprehensively compiled.Stereochemical aspects and mass spectrometric fragmentation patterns are discussed in detail to facilitate identifications of hitherto unknown compounds. Synthetic approaches to spiroacetals are classified and reviewed. Last but not least, facts and speculations on the biosynthesis of volatile spiroacetals are presented.