3 research outputs found
Recommended from our members
The reactive species interactome: evolutionary emergence, biological significance, and opportunities for redox metabolomics and personalized medicine
SIGNIFICANCE: Oxidative stress is thought to account for aberrant redox homeostasis and contribute to aging and disease. However, more often than not administration of antioxidants is ineffective, suggesting our current understanding of the underlying regulatory processes is incomplete. Recent Advances. Similar to reactive oxygen and nitrogen species (ROS, RNS), reactive sulfur species (RSS) are now emerging as important signaling molecules, targeting regulatory cysteine redox switches in proteins, affecting gene regulation, ion transport, intermediary metabolism and mitochondrial function. To rationalize the complexity of chemical interactions of reactive species with themselves and their targets and help define their role in systemic metabolic control, we here introduce a novel integrative concept coined the reactive species interactome (RSI). The RSI is a primeval multi-level redox-regulatory system whose architecture, together with the physicochemical characteristics of its constituents, allows efficient sensing and rapid adaptation to environmental changes and various other stresses to enhance fitness and resilience at the local and whole-organism level.
CRITICAL ISSUES: To better characterise the RSI-related processes that determine fluxes through specific pathways and enable integration, it is necessary to disentangle the chemical biology and activity of reactive species (including precursors and reaction products), their targets, communication systems and effects on cellular, organ and whole-organism bioenergetics using systems-level/network analyses.
FUTURE DIRECTIONS: Understanding the mechanisms through which the RSI operates will enable a better appreciation of the possibilities to modulate the entire biological system; moreover, unveiling molecular signatures that characterize specific environmental challenges or other stresses will provide new prevention/intervention opportunities for personalized medicine
The beginnings of proto-metabolism at the origin of life in alkaline hydrothermal vents
The origin of life is still one of the most exciting scientific quests, one that has deep implications that go far beyond science itself. This thesis explores the possible origins of carbon and energy proto-metabolism in Hadean alkaline hydrothermal vents. I first explore the catalytic properties of Fe(Ni)S minerals in the presence of geologically sustained proton gradients, which lower the kinetic barrier to the reaction between H2 and CO2. This could have promoted nonenzymatic pathways analogous to the acetyl CoA pathway and reverse incomplete Krebs cycle, which drive carbon metabolism in arguably some of the most ancient microorganisms (methanogenic archaea). One of the predicted prebiotic products is thioacetate, which we have shown can be nonenzymatically phosphorolysed to acetyl phosphate (AcP). AcP is widely used in bacteria and archaea as a key intermediary between acetyl CoA and ATP, driving substrate-level phosphorylation of ADP. Its simple structure and high phosphorylating potential suggest it could have acted as a primordial ATP analogue, driving energy metabolism at the beginnings of proto-metabolism. The thesis then explores the phosphorylating capabilities of AcP on ribose, adenosine and ADP, followed by a study on the condensing capabilities of AcP with glycine and AMP. Finally, I explore how carbon and energy metabolism could have interacted during early abiogenesis. The formose reaction nonenzymatically synthesises sugars (carbon metabolism) from formaldehyde, one of the first products of CO2 reduction. AcP could hypothetically direct the formose reaction towards biologically interesting sugars such as ribose using AcP (energy metabolism), rather than the much larger and ramified tars often claimed to be its main products. I show how Hadean alkaline hydrothermal vents could have promoted non-enzymatic pathways analogous to the acetyl CoA pathway and reverse incomplete Krebs cycle. I report that AcP can non-enzymatically phosphorylate a variety of biomolecules, but does not promote the polymerisation of glycine or AMP. Most strikingly, I show that AcP can indeed direct the formose reaction towards the synthesis of pentoses such as ribose