Synthesis of novel polyketides as source of new antibiotics.
	Use metabolic engineering principles to treat human diseases - ex. Celi ac Sprue (autoimmune; exclude gluten).

	Use metabolic assembly lines to develop cost-effective methods of production of known drugs.
	Create new drug-like molecules.
	Identify rate-limiting steps in gastrointestinal gluten metabolism.
	Identify immunotoxic intermediates that build up.

	Erythromycin (anti-bacterial) - new analogs have been prepared and provide a starting point for new antibiotics
	Epothilone (anti-cancer) - availability allows initiation of human clinical studies
	Novel mode of treatment using specific peptidases
	Ongoing lab and clinical studies

	New horizons in disease and cancer treatment
	Potential to improve quality of life of millions of patients suffering from Celiac Sprue

Abstract:

Metabolic engineering refers to the rational manipulation of metabolism to achieve a practically useful outcome. Whereas applications of this emerging discipline in the chemical and processing industry are gaining widespread recognition, equally important is the scope of metabolic engineering in biomedicine. Two examples of such activities will be presented.  

Polyketides are a large family of structurally diverse natural products with a broad range of biological activities. Over the past half-century they have been a fertile source of new antibiotics. Recent studies have highlighted the assembly-line mechanisms by which these complex molecules are biosynthesized. In turn these enzymatic assembly lines have been exploited by the metabolic engineer to develop cost-effective methods for producing known polyketide drugs as well as to create new drug-like molecules. Recent progress in these directions will be illustrated via the example of the well-known antibacterial agent erythromycin and the emerging anti-cancer agent epothilone.  

Although the metabolic basis for many human diseases is well established, the power of metabolic engineering principles to treat such disorders is not generally appreciated. To illustrate the point, recent studies on engineering gluten metabolism in Celiac Sprue patients will be discussed. Celiac Sprue is a widespread lifelong autoimmune disease of the small intestine for which the only known treatment is strict exclusion of all forms of dietary gluten. The underlying pathophysiology of this inheritable disorder is not well understood; however, by identifying the rate-limiting steps in gastrointestinal gluten metabolism and characterizing the immunotoxic intermediates that build up in the process, a novel mode of treating Celiac Sprue has been proposed. Ongoing laboratory and clinical studies aimed at testing this proposal are highlighting the opportunities of targeting complex chronic human diseases at the metabolic level.

Return to Table of Contents