One‐carbon metabolism, folate, zinc and translation

Abstract

The translation process, central to life, is tightly connected to the one-carbon (1-C) metabolism via a plethora of macromolecule modifications and specific effectors. Using manual genome annotations and putting together a variety of experimental studies, we explore here the possible reasons of this critical interaction, likely to have originated during the earliest steps of the birth of the first cells.Methionine, S-adenosylmethionine and tetrahydrofolate dominate this interaction. Yet, 1-C metabolism is unlikely to be a simple frozen accident of primaeval conditions. Reactive 1-C species (ROCS) are buffered by the translation machinery in a way tightly associated with the metabolism of iron-sulfur clusters, zinc and potassium availability, possibly coupling carbon metabolism to nitrogen metabolism. In this process, the highly modified position 34 of tRNA molecules plays a critical role. Overall, this metabolic integration may serve both as a protection against the deleterious formation of excess carbon under various growth transitions or environmental unbalanced conditions and as a regulator of zinc homeostasis, while regulating input of prosthetic groups into nascent proteins. This knowledge should be taken into account in metabolic engineering.

Zinc, an unexpected integrator of metabolism?

“…What if one of the overlooked components played a critical role in major life processes? We have now hints that zinc, as the divalent cation Zn 2+ and not monitored in the vast majority of growth media or biochemical assays, is integrating major metabolic features via the coordination of translation with one‐carbon metabolism [Danchin et al 2020 and Fig. 1].…”

“…In a surprising turn of things, the intricate coupling between one‐carbon metabolism and translation – initially witnessed as the omnipresent requirement for a methionine residue at the start of translated polypeptides – revealed that the connection was established via the homeostasis of Zn 2+ (Danchin et al 2020, and Fig. 1), mediated by the ribosomes as a main Zn 2+ store (Hensley et al , 2012).…”

“…This strongly argues for a functional dependency relating translation, 1‐C metabolism and zinc homeostasis. Analysis of the underlying enzyme activities revealed that this possibly happened via management of iron‐sulfur clusters (Danchin et al 2020). The key metabolites of this network are formaldehyde, methionine, S‐adenosylmethionine (AdoMet) and tetrahydrofolate.…”

On the Track of the Missing tRNA Genes: A Source of Non-Canonical Functions?

“…However, this may not be the only cause if bacteria and archaea tRNAs are considered, as this modification is only present in tRNA Arg ACG. Most tRNA modifications are directly linked to the metabolic state through the requirement of key cofactor molecules, from which S-adenosylmethionine as chemical group donor and thiol source is the main paradigm ( Helm and Alfonzo, 2014 ; Danchin et al, 2020 ). However, adenosine deamination, Q/G transglycosylation (in eukaryotes) and pseudouridylation (that also involves a transglycosylation mechanism) ( Veerareddygari et al, 2016 ) are not directly related to the metabolic state of the cell.…”

“…Within the scope of this review, we would like to emphasize that the enzymes involved in a large number of post-transcriptional modifications of tRNA (methylation, thiolation and incorporation of amino acid derivatives, dihydrouridine synthase, among others) require cofactors that constitute key molecules in metabolic pathways. Within them, it is worth mentioning S-adenosylmethionine (AdoMet), folate and NADPH (see Figure 1 ) ( Helm and Alfonzo, 2014 ; Danchin et al, 2020 ).…”