Metabolic Perturbation of an Essential Pathway: Evaluation
of a Glycine Precursor of Coenzyme A
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Abstract
Pantetheine and its
corresponding disulfide pantethine play a key
role in metabolism as building blocks of coenzyme A (CoA), an essential
cofactor utilized in ∼4% of primary metabolism and central
to fatty acid, polyketide, and nonribosomal peptide synthases. Using
a combination of recombinant engineering and chemical synthesis, we
show that the disulfide of <i>N</i>-pantoylglycyl-2-aminoethanethiol
(GlyPan), with one fewer carbon than pantetheine, can rescue a mutant E. coli strain MG1655Δ<i>panC</i> lacking a functional pantothenate synthetase. Using mass spectrometry,
we show that the GlyPan variant is accepted by the downstream CoA
biosynthetic machinery, ultimately being incorporated into essential
acyl carrier proteins. These findings point to further flexibility
in CoA-dependent pathways and offer the opportunity to incorporate
orthogonal analogues