How to Advertise
Home | This Week's Contents  |  C&EN ClassifiedsSearch C&EN Online

 
Millennium Special Report
C&EN 75th Anniversary Issue
 
Related Stories
Personal Care: Pure & Sweet
[C&EN, April 16, 2001]

NATURALLY COMBINATORIAL
[C&EN, October 30, 2000]

Using Synthesis To Explain Life's Unsolved Mysteries
[C&EN, July 26, 1999]

Related People
Jon S. Thorson

Dimitar B. Nikolov

Christopher T. Walsh

Chi-Huey Wong

Ole Hindsgaul

E-mail this article to a friend
Print this article
E-mail the editor
 
 
 
 Table of Contents
 C&EN Classifieds
 News of the Week
 Cover Story
 Editor's Page
 Business
 Government & Policy
 Science/Technology
 Concentrates
  Business
  Government & Policy
  Science/Technology
 Education
 ACS News
 Calendars
 Books
 Digital Briefs
 ACS Comments
 Career & Employment
 Special Reports
 Letters
 People
 Newscripts
 Nanotechnology
 What's That Stuff?
 Pharmaceutical Century

 Hot Articles
 Safety  Letters
 Chemcyclopedia

 Back Issues

 How to Subscribe
 Subscription Changes
 About C&EN
 Copyright Permission
 E-mail webmaster
NEWS OF THE WEEK
SYNTHESIS
June 4, 2001
Volume 79, Number 23
CENEAR 79 23 pp. 11
ISSN 0009-2347
[Previous Story] [Next Story]

NONNATURAL 'NATURAL' PRODUCTS
Glycorandomization may be simple alternative to current methods

STU BORMAN

A promising new strategy could permit libraries of natural-product-like compounds derivatized with nonnatural sugar groups to be generated more quickly and conveniently than is currently possible.

Attached sugar groups help determine the biological activity of a wide variety of pharmaceutically interesting natural products--including antibiotic and anticancer agents such as calicheamicin, doxorubicin, and vancomycin. Researchers would like to be able to modify these carbohydrate groups to produce libraries of nonnatural analogs with potentially useful new properties.

However, the two major techniques currently used to make such modifications--total organic synthesis and combinatorial biosynthesis--have significant limitations. So natural-product-like compounds decorated with variant sugars have not been widely accessible.

Now, biosynthetic chemist Jon S. Thorson and coworkers at Memorial Sloan-Kettering Cancer Center, New York City, have developed a technique called "glycorandomization" that may make it possible to produce such compounds more easily. Thorson recently moved to the University of Wisconsin, Madison.

The researchers, in collaboration with Memorial Sloan-Kettering structural biologist Dimitar B. Nikolov and coworkers, took a key sugar-activating enzyme with high selectivity for natural sugar substrates and engineered it to recognize nonnatural sugars as substrates [Nat. Struct. Biol., 8, 545 (2001)]. In preliminary studies, they've since used that engineered enzyme to create libraries of glycorandomized natural-product-like compounds containing nonnatural sugars.

In the glycorandomization approach, two enzymes borrowed from a bacterial biosynthetic pathway are commandeered to produce nonnatural-sugar-containing compounds. In this pathway, a nucleotidyltransferase enzyme first activates a sugar phosphate substrate by catalyzing its transformation into a nucleotide diphosphosugar. A glycosyltransferase then takes the activated sugar and catalyzes its addition to an aglycon (noncarbohydrate precursor) of a natural product.

Glycosyltransferases tend to recognize nonnatural as well as natural nucleotide diphosphosugars as substrates. But nucleotidyltransferases generally don't recognize modified sugar phosphates. Nikolov, Thorson, and coworkers have now engineered a more "promiscuous" nucleotidyltransferase capable of recognizing nonnatural as well as natural sugar phosphates as substrates.

To carry out a glycorandomization, one chemically converts natural sugar phosphates into nonnatural ones. These are fed to the engineered nucleotidyltransferase, which catalyzes their activation. The resulting nucleotide diphosphosugars are then passed to a glycosyltransferase, which catalyzes their addition to aglycons to form libraries of nonnatural-sugar-containing "natural" products.

Producing such libraries by total synthesis is complicated, time-consuming, and expensive. And with combinatorial biosynthesis--in which microbial natural product biosynthetic pathways are genetically modified to produce nonnatural analogs--product variability is restricted by inherent limitations of the microorganisms' biosynthetic machinery.

In preliminary studies, nonnatural-sugar variants of erythromycin and novobiocin have been generated in Thorson's laboratory and nonnatural-sugar-containing vancomycins have been created in a collaboration between Thorson's group and that of biological chemistry professor Christopher T. Walsh at Harvard Medical School. "None of these examples has been published," Thorson says, "as we are working to establish the biological activities of the variants produced."

Thorson notes that glycorandomization "really draws upon all the terrific chemo-enzymatic nucleotide sugar syntheses established earlier by Chi-Huey Wong," professor of chemistry at Scripps Research Institute.

Asked to comment on the glycorandomization technique, chemistry professor Ole Hindsgaul of the University of Alberta, Edmonton, says, "It's elegant molecular genetics--getting an enzyme to do a chemically intractable reaction." It remains to be demonstrated "that the modified compounds will be useful," he adds. "But these analogs would cost you hundreds of thousands of dollars to make in industry if you were to make them one at a time. They are simply not accessible in any other pragmatic way."



Top


Chemical & Engineering News
Copyright © 2001 American Chemical Society


How to Advertise
Home | Table of Contents | News of the Week | Cover Story
Business | Government & Policy | Science/Technology
Chemical & Engineering News
Copyright © 2001 American Chemical Society - All Right Reserved
1155 16th Street NW • Washington DC 20036 • (202) 872-4600 • (800) 227-5558


CASChemPortChemCenterPubs Page