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
