Substrate-Assisted and Enzymatic Pretransfer Editing of Nonstandard Amino Acids by Methionyl-tRNA Synthetase

Biochemistry
Grant B FortowskyJames W Gauld

Abstract

Aminoacyl-tRNA synthetases (aaRSs) are central to a number of physiological processes, including protein biosynthesis. In particular, they activate and then transfer their corresponding amino acid to the cognate tRNA. This is achieved with a generally remarkably high fidelity by editing against incorrect standard and nonstandard amino acids. Using docking, molecular dynamics (MD), and hybrid quantum mechanical/molecular mechanics methods, we have investigated mechanisms by which methionyl-tRNA synthetase (MetRS) may edit against the highly toxic, noncognate, amino acids homocysteine (Hcy) and its oxygen analogue, homoserine (Hse). Substrate-assisted editing of Hcy-AMP in which its own phosphate acts as the mechanistic base occurs with a rate-limiting barrier of 98.2 kJ mol(-1). This step corresponds to nucleophilic attack of the Hcy side-chain sulfur at its own carbonyl carbon (CCarb). In contrast, a new possible editing mechanism is identified in which an active site aspartate (Asp259) acts as the base. The rate-limiting step is now rotation about the substrate's aminoacyl Cβ-Cγ bond with a barrier of 27.5 kJ mol(-1), while for Hse-AMP, the rate-limiting step is cleavage of the CCarb-OP bond with a barrier of 30.9 kJ mol(-1). ...Continue Reading

References

Jul 10, 1981·Nucleic Acids Research·H Jakubowski, A R Fersht
Jan 22, 1998·Current Opinion in Structural Biology·S Cusack
Dec 3, 1999·Science·M Ibba, D Söll
Jul 6, 2000·Nature Structural Biology·R SankaranarayananD Moras
Mar 29, 2003·Journal of Molecular Biology·Chun-Mei ZhangYa-Ming Hou
Dec 16, 2003·The Journal of Biological Chemistry·Ryuya FukunagaShigeyuki Yokoyama
Mar 5, 2004·Cellular and Molecular Life Sciences : CMLS·H Jakubowski
Apr 14, 2004·Proceedings of the National Academy of Sciences of the United States of America·Kirk BeebePaul Schimmel
May 12, 2005·The Journal of Biological Chemistry·Benfang Ruan, Dieter Söll
Aug 10, 2005·The Journal of Biological Chemistry·Songon An, Karin Musier-Forsyth
Sep 13, 2005·Nature Structural & Molecular Biology·Kotaro NakanishiOsamu Nureki
Oct 4, 2005·Journal of Computational Chemistry·David A CaseRobert J Woods
May 16, 2006·Journal of Molecular Biology·Ryuya Fukunaga, Shigeyuki Yokoyama
May 10, 2008·Accounts of Chemical Research·Maria J Ramos, Pedro A Fernandes
Jun 5, 2008·FEMS Microbiology Reviews·Corinne D Hausmann, Michael Ibba
May 12, 2009·Molekuliarnaia biologiia·M G Safro, N A Moor
May 28, 2010·The Journal of Biological Chemistry·Anand Minajigi, Christopher S Francklyn
Nov 17, 2010·Nature Reviews. Microbiology·Noah M ReynoldsMichael Ibba
Jul 20, 2011·The Journal of Biological Chemistry·Byung Ran SoKarin Musier-Forsyth
Nov 19, 2011·Wiley Interdisciplinary Reviews. RNA·Hieronim Jakubowski
Jan 27, 2012·ACS Chemical Biology·Varun DewanKarin Musier-Forsyth
Feb 15, 2012·The Journal of Physical Chemistry. B·Jing WangMin Guo
Mar 31, 2012·The Journal of Physical Chemistry. B·Sandeep KumarKarin Musier-Forsyth
Jun 27, 2012·Journal of Biomolecular Structure & Dynamics·Sindrila Dutta Banik, Nilashis Nandi
Nov 29, 2012·The Journal of Physical Chemistry. B·Sandeep KumarKarin Musier-Forsyth
May 1, 2006·Journal of Chemical Theory and Computation·Thom VrevenMichael J Frisch

❮ Previous
Next ❯

Citations

Oct 11, 2016·Organic & Biomolecular Chemistry·Mark D VaughanJ F Honek
Nov 15, 2018·Physiological Reviews·Hieronim Jakubowski
Oct 30, 2020·European Respiratory Review : an Official Journal of the European Respiratory Society·Alice HadchouelJacques de Blic

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.