Tuesday, October 31, 2006

Analogue resistant mutants and the discovery of metabolic regulation are inextricably linked in history.

The History of Using Metabolic Analogs to Reveal Regulation of Metabolism.


Metabolic analogues
are compounds that structurally resemble natural metabolites.

A name for a metabolic analogue that interferes with cell functions is antimetabolite.

Antimetabolities will often inhibit cell growth.

Sulfa drugs were perhaps the first antimetabolites.



In 1958, Ed Adelberg discovered that Escherichia coli MUTANTS, that had been selected as being resistant to growth inhibition by toxic metabolic analogues, secreted excess quantities of certain metabolites into their growth medium that the wild-type parental strains DID NOT secrete.


For instance, E. coli mutants selected for resistance to p-fluorophenylalanine secreted tyrosine and only tyrosine into the medium.

p-Fluorophenylalanine is a tyrosine analogue.

The compounds secreted by E. coli mutants differed when different types of antimetabolite were used to select mutants.

Ethioninione resistant mutants secreted methionine. (The structure of ethionine is Ethyl replacing the Methyl in methioninine.)

The patterns of secretion suggested to Adelberg that resistance was based on COMPETITION between metabolite and analogue.

Interestingly, metabolic analogues were provided to Ed Edelberg by Arthur Pardee, one of the discovers of feed-back inhibitable biosynthetic enzymes (allosteric enzymes).

In 1960 Pardee reported 3-Methylaspartic acid as a potent antimetabolite of aspartic acid in pyrimidine biosynthesis, showing these ideas are not confined to amino acid pathways.

Selection of bacterial mutants which excrete antagonists of antimetabolites.
J Bacteriol. 1958 Sep;76(3):326.Click here to read Links
ADELBERG EA
Now marvellously available online via Pubmed
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=13575393

Famously, Pardee and Yates had discovered feedback-inhibition in 1956, in a key paper revealing the existence of biochemical regulation.

Dick Yates went on to work in applied microbiology in Wilmington DE, and the Pundit is honoured to have met this gracious American scientist.

J Biol Chem. 1956 Aug;221(2):757-70.
Control of pyrimidine biosynthesis in Escherichia coli by a feed-back mechanism.
PARDEE AB, YATES RA.
PMID: 13357469 [PubMed - OLDMEDLINE for Pre1966]
http://www.jbc.org/cgi/reprint/221/2/757

Related Links
Pyrimidine biosynthesis in Escherichia coli. [J Biol Chem. 1956]
PMID:13357468
Studies on the biosynthesis of bacterial and viral pyrimidines. IV.
Utilization of pyrimidine bases and nucleosides by bacterial mutants. [J Biol
Chem. 1957] PMID:13475346
3-Methylaspartic acid as a potent antimetabolite of aspartic acid in
pyrimidine biosynthesis. [J Biol Chem. 1960] PMID:13786646

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