The Impact of Non-Enzymatic Reactions and Enzyme Promiscuity on Cellular Metabolism during (Oxidative) Stress Conditions.

Gabriel Piedrafita,Markus Keller,Markus Ralser

doi:10.3390/biom5032101

Gabriel Piedrafita, Markus Keller + Show 1 more

Open Access

https://doi.org/10.3390/biom5032101

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Journal: Biomolecules	Publication Date: Sep 10, 2015
Citations: 205	License type: CC BY 4.0

Affiliation: University of Cambridge, The Francis Crick Institute

Abstract

Cellular metabolism assembles in a structurally highly conserved, but functionally dynamic system, known as the metabolic network. This network involves highly active, enzyme-catalyzed metabolic pathways that provide the building blocks for cell growth. In parallel, however, chemical reactivity of metabolites and unspecific enzyme function give rise to a number of side products that are not part of canonical metabolic pathways. It is increasingly acknowledged that these molecules are important for the evolution of metabolism, affect metabolic efficiency, and that they play a potential role in human disease—age-related disorders and cancer in particular. In this review we discuss the impact of oxidative and other cellular stressors on the formation of metabolic side products, which originate as a consequence of: (i) chemical reactivity or modification of regular metabolites; (ii) through modifications in substrate specificity of damaged enzymes; and (iii) through altered metabolic flux that protects cells in stress conditions. In particular, oxidative and heat stress conditions are causative of metabolite and enzymatic damage and thus promote the non-canonical metabolic activity of the cells through an increased repertoire of side products. On the basis of selected examples, we discuss the consequences of non-canonical metabolic reactivity on evolution, function and repair of the metabolic network.

Highlights

During its lifespan, a cell is exposed to many hazards and changes in the environment
A second aspect of the susceptibility of metabolism concerns non-enzymatic reactions that occur as part of normal metabolism or through non-specific chemical reactivity but that contribute to canonical metabolic pathways [69,70]
Met is a biological scavenger of reactive oxygen species (ROS), proposing an adaptive role of methionyl-tRNA synthetase (MetRS) promiscuity and controlled Met-misacylation in coping with oxidative damage (Table 1)

Summary

Introduction

A cell is exposed to many hazards and changes in the environment. These include varying pH and temperature, osmotic imbalances, radiation, drought, starvation, contact with deleterious or toxic chemicals, or biotic interactions with other species. These stress situations can manifest as an acute pulse, or be sustained over time, and can affect cellular functioning and impair cell growth, replicative capabilities, and/or promote aging. Cellular metabolites and the flux through metabolic pathways are affected. Since metabolism is a basal property of life and a main driving force during evolution, being the closest-to-phenotype cellular attribute, and given the reactive nature of many metabolites, the identification of stress-related metabolic processes appears to be of fundamental importance

Chemical Damage to Metabolites

Other Forms of Metabolite Damage

Non-Enzymatic Metabolic Reactions Are Affected by Stress Conditions

Enzymes That Change Substrate Specificity during Stress Conditions

Changing Activity and Metabolic Switches

Findings

Conclusions