Pyridoxal 5′-Phosphate-Dependent Enzymes at the Crossroads of Host–Microbe Tryptophan Metabolism

Abstract

The chemical processes taking place in humans intersects the myriad of metabolic pathways occurring in commensal microorganisms that colonize the body to generate a complex biochemical network that regulates multiple aspects of human life. The role of tryptophan (Trp) metabolism at the intersection between the host and microbes is increasingly being recognized, and multiple pathways of Trp utilization in either direction have been identified with the production of a wide range of bioactive products. It comes that a dysregulation of Trp metabolism in either the host or the microbes may unbalance the production of metabolites with potential pathological consequences. The ability to redirect the Trp flux to restore a homeostatic production of Trp metabolites may represent a valid therapeutic strategy for a variety of pathological conditions, but identifying metabolic checkpoints that could be exploited to manipulate the Trp metabolic network is still an unmet need. In this review, we put forward the hypothesis that pyridoxal 5′-phosphate (PLP)-dependent enzymes, which regulate multiple pathways of Trp metabolism in both the host and in microbes, might represent critical nodes and that modulating the levels of vitamin B6, from which PLP is derived, might represent a metabolic checkpoint to re-orienteer Trp flux for therapeutic purposes.

Molecular Mechanisms of Microbiota-Mediated Pathology in Irritable Bowel Syndrome

“…Vitamin B6 is a water-soluble vitamin that is present in several forms [ 230 ]. The bioactive form, pyridoxal 5′-phosphate, serves as a coenzyme in a variety of essential cellular processes, including those related to amino acids, carbohydrates, and lipid metabolism [ 231 ], while its metabolic pathways are mediated by multiple bacterial species and their enzymes [ 230 , 231 ]. A deficiency of vitamin B6 is likely associated with an inflammatory condition [ 232 ], thus it might be involved in the inflammation-mediated pathology of IBS.…”

The Microbiota/Host Immune System Interaction in the Nose to Protect from COVID-19

“…Besides probiotic administration, an alternative strategy would be represented by the modulation of nutrients upon which both the host and the microbiota converge for functional cross-regulation. One such nutrient is represented by tryptophan (Trp), an essential amino acid in mammals, which is the substrate of a multitude of host and microbial metabolic pathways in the generation of bioactive molecules [ 58 , 59 , 60 ]. The Trp metabolic pathways play a critical role in immune regulation and immune tolerance.…”

“…Therefore, it remains to be seen whether AhR antagonism or agonism would be the most promising therapeutic strategy in COVID-19. Whatever the case, it is important to consider the Trp metabolism as a whole, thus including the host and microbial metabolic pathways, as alterations of the Trp flux may result in pathological conditions [ 60 , 74 ]. The balance between the IDO1 and AhR pathways represents a surrogate for the status of the microbiota and the local immune system and a predictive factor for the susceptibility to infection and the disease course.…”

Tryptophan Metabolism as a Pharmacological Target

“…Such is the case with carbidopa that irreversibly binds to free PLP and PLP-dependent enzymes [43]. Moreover, recently a central function for vitamin B6 and PLP in the homeostatic host-microbiota crosstalk through L-Trp metabolism has been shown [44]. It may be hazardous to exacerbate an imbalance in L-Trp metabolism in patients since dysregulation of host-microbiota homeostasis has shown its involvement in many diseases.…”