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Maddocks, O.D.K., Athineos, D., Cheung, E.C., Lee, P., Zhang, T., van den Broek, N.J.F., Mackay, G.M., Labuschagne, C.F., Gay, D., Kruiswijk, F., Blagih, J., Vincent, D.F., Campbell, K.J., Ceteci, F., Sansom, O.J., Blyth, K. and Vousden, K.H. (2017) Modulating the Therapeutic Response of Tumours to Dietary Serine and Glycine Starvation. Nature, 19, 372-376.
https://doi.org/10.1038/nature22056

has been cited by the following article:

• TITLE: The Paradoxical Effect of Paraquat on Leucyl-tRNA Levels in E. coli Provides New Insights for Amino Acid Therapy in Humans

  AUTHORS: Babu V. Bassa, Olen R. Brown

  KEYWORDS: E. coli, Leucine, Leucyl-tRNA, Paraquat, Leucine Abundance, Amino Acid Starvation, Cancer Therapy

  JOURNAL NAME: CellBio, Vol.7 No.4, October 20, 2018

  ABSTRACT: Dihydroxyacid dehydratase (DHAD), the rate-limiting enzyme in the synthesis of branched-chain (BCA) amino acids in bacteria and plants, is sensitive to oxyradical toxicity. Oxidant stress reversibly inactivates DHAD and causes starvation for BCA and reversible cessation of growth in Escherichia coli [1][2]. To better understand the underlying toxicity mechanisms, we have determined the cellular concentrations of charged-tRNAs for BCA, in E. coli treated with the redox-active chemical, paraquat. Contrary to expectation, in the paraquat-treated cells, the concentration of only charged leucyl-tRNA decreased dramatically; whereas, the concentrations of the other BCAs (valine and isoleucine) increased. This paradoxical result, the “paraquat effect” can be best explained if leucine is the most abundant amino acid in the E. coli proteins and therefore the rate-limiting building block in their synthesis. Based on this assumption, we investigated the concentration of free amino acids in E. coli and their relative abundances in E. coli proteins. Protein amino acid frequencies were determined by analyzing one-hundred gene bank protein sequences with software developed as described in Methods. Leucine is the most abundant amino acid in the E. coli proteins (10%) and consequently, the cellular free leucine concentration is smaller and the native charged-leucyl-tRNA levels are much higher than those of valine and isoleucine. This has relevance to humans because: leucine-deprivation was shown to be beneficial in tumor suppression [3], and leucine-supplementation was beneficial in the recovery from exercise-induced muscle loss [4][5], and leucine also occurs at a higher frequency in almost all human proteins. In three human protein categories, we examined it ranged from 9% to 17%. This predominance of leucine in proteins would make cells vulnerable to impairment of the leucine pools and could explain our results in E. coli and some of the biological effects of free leucine in humans.