Promiscuity of Metabolites: An Obvious but Often Overlooked Fact

Dear Colleagues,

The fact that many metabolites can be recognized by multiple proteins, both as substrates of enzymatic reactions and as ligands on regulatory sites, is a well known but often overlooked fact. The enormous importance of the promiscuity of metabolites can be appreciated by considering a series of apparently trivial facts, which in reality underlie the organisation, functioning and regulation of metabolic networks. The presence of well-defined metabolic pathways, their crosstalk, and their reciprocal regulation are due to nothing more than metabolic promiscuity. Even from an evolutionary point of view, the phenomenon is important as it is the basis for the appearance of new metabolic pathways. Gene duplication and divergence have led over time to the emergence of new metabolic enzymes and regulatory proteins. Promiscuous secondary activities can become important for the fitness of the organism, and mutations in the proteins involved can lead to the emergence of new functions. Innovation-amplification-divergence phenomena where an ancestor protein with a weak promiscuous activity acquires a new activity, or vice versa promiscuous ancestral proteins that acquire greater specificity following the accumulation of mutations are the basis of current metabolic networks. These same phenomena have recently begun to be explored also from a biotechnological point of view.

The promiscuity of metabolites is obviously a two-sided coin: on the one hand we have the proteins or, more generally, the target macromolecules, on the other the metabolites themselves. Many studies have been performed on what are the structural motifs of proteins that bind the same metabolite or the same class of metabolites. One of the most important and studied examples is the Rossmann fold, a super-secondary structure capable of binding the ADP component of dinucleotides such as FAD, NAD and NADP. Additionally, similarly many other super-secondary motifs capable of binding specific small molecules, or parts of them, are described in the literature. The current availability of three-dimensional structures, including the enormous number of structures calculated by artificial intelligence algorithms, places the research community in the position of being able to analyze in detail what are the molecular basis of metabolic promiscuity at very large scale. From the point of view of the metabolites, the availability of an ever-increasing number of information on the thermodynamic and functional data of the binding of the same metabolite to different targets is laying the foundations for an in-depth study of the molecular bases (or chemical descriptors) of promiscuity.

Furthermore, it is not necessary to remember that the phenomenon of promiscuity does not concern only endogenous metabolites, but also exogenous ones. For drugs in particular, the importance of the promiscuity of these molecules is increasingly evident: their ability to bind different target proteins is the basis of toxicity phenomena. However, it is increasingly being appreciated that often the ability to bind multiple molecules is important for the therapeutic effects of many molecules, as well as of pharmacological repositioning.

Therefore, this Special Issue aims to publish original research articles and insightful reviews concerning metabolic promiscuity. Manuscripts describing new phenomena and evidence of metabolic promiscuity, which provide insights or innovative study strategies of this vast topic, will be taken into consideration. In vitro and in vivo studies will be considered, as well as theoretical or computational ones. In this latter case, it will be necessary to compare it with experimental data, including those deriving from large databases, or with already known algorithms. This Special Issue will cover topics including, but not limited to, the following:

• Molecular basis of metabolic promiscuity;
• New phenomena of metabolic promiscuity;
• Effect of mutations on metabolic promiscuity;
• Metabolic promiscuity in pathological states;
• Biotechnological use of metabolic promiscuity;
• The importance of the metabolic promiscuity of drugs and their metabolites;
• Algorithms for the prediction of metabolic promiscuity or its effects.

Prof. Dr. Luigi Leonardo Palese
Prof. Dr. Antonio Gnoni
Guest Editors

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• metabolites
• biological promiscuity
• metabolism
• molecular evolution
• catalysis
• drug discovery
• drug repositioning
• drug resistance
• structure-activity relationship
• binding sites
• protein binding
• thermodynamics
• metabolome
• metabolomics