Convincing demonstrations that an end-product can inhibit the initial enzymatic reaction was identified for pathways synthesizing isoleucine-valine 8 by Edwin Umbarger in 1956, and for pyrimidines by Yates and Pardee where the first enzyme in the seven successive enzyme-catalyzed reactions (aspartate transcarbamylase, ATCase) is feedback inhibited by added uracil.9
As expected mutant bacteria could accumulate the metabolite prior
to their missing reaction, but only when the end product of the
pathway was not provided. This observation led to perhaps the first
review on regulation of metabolism.10 Feedback mechanisms have now been verified for numerous pathways.11 Some of these are complex, involving metabolic branching as investigated by Earl
Stadtman.12 A remarkable example is ribonucleotide reductase,
whose feedback regulation Peter Reichard demonstrated balances
production of the four deoxynucleotide building blocks of DNA
from alternative substrates.13