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Abstract:
The promiscuous activities of enzymes provide fertile ground for the
evolution of new metabolic pathways. Here, we systematically explore the
ability of E. coli to harness underground metabolism to compensate for
the deletion of an essential biosynthetic pathway. By deleting all
threonine deaminases, we generated a strain in which isoleucine
biosynthesis was interrupted at the level of 2-ketobutyrate. Incubation
of this strain under aerobic conditions resulted in the emergence of a
novel 2-ketobutyrate biosynthesis pathway based upon the promiscuous
cleavage of O-succinyl-L-homoserine by cystathionine gamma-synthase
(MetB). Under anaerobic conditions, pyruvate formate-lyase enabled
2-ketobutyrate biosynthesis from propionyl-CoA and formate.
Surprisingly, we found this anaerobic route to provide a substantial
fraction of isoleucine in a wildtype strain when propionate is available
in the medium. This study demonstrates the selective advantage
underground metabolism offers, providing metabolic redundancy and
flexibility which allow for the best use of environmental carbon
sources.
