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Kinetics of d-Amino Acid Incorporation in Translation.

Abstract：

:Despite the stereospecificity of translation for l-amino acids (l-AAs) in vivo, synthetic biologists have enabled ribosomal incorporation of d-AAs in vitro toward encoding polypeptides with pharmacologically desirable properties. However, the steps in translation limiting d-AA incorporation need clarification. In this work, we compared d- and l-Phe incorporation in translation by quench-flow kinetics, measuring 250-fold slower incorporation into the dipeptide for the d isomer from a tRNAPhe-based adaptor (tRNAPheB). Incorporation was moderately hastened by tRNA body swaps and higher EF-Tu concentrations, indicating that binding by EF-Tu can be rate-limiting. However, from tRNAAlaB with a saturating concentration of EF-Tu, the slow d-Phe incorporation was unexpectedly very efficient in competition with incorporation of the l isomer, indicating fast binding to EF-Tu, fast binding of the resulting complex to the ribosome, and rate-limiting accommodation/peptide bond formation. Subsequent elongation with an l-AA was confirmed to be very slow and inefficient. This understanding helps rationalize incorporation efficiencies in vitro and stereospecific mechanisms in vivo and suggests approaches for improving incorporation.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Liljeruhm J,Wang J,Kwiatkowski M,Sabari S,Forster AC

doi

10.1021/acschembio.8b00952

subject

Has Abstract

pub_date

2019-02-15 00:00:00

pages

204-213

issue

2

eissn

1554-8929

issn

1554-8937

journal_volume

14

pub_type

杂志文章

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