Membrane transporters in a human genome-scale metabolic knowledgebase and their implications for disease

Abstract

Membrane transporters enable efficient cellular metabolism, aid in nutrient sensing, and have been associated with various diseases, such as obesity and cancer. Genome-scale metabolic network reconstructions capture genomic, physiological, and biochemical knowledge of a target organism, along with a detailed representation of the cellular metabolite transport mechanisms. Since the first reconstruction of human metabolism, Recon 1, published in 2007, progress has been made in the field of metabolite transport. Recently, we published an updated reconstruction, Recon 2, which significantly improved the metabolic coverage and functionality. Human metabolic reconstructions have been used to investigate the role of metabolism in disease and to predict biomarkers and drug targets. Given the importance of cellular transport systems in understanding human metabolism in health and disease, we analyzed the coverage of transport systems for various metabolite classes in Recon 2. We will review the current knowledge on transporters (i.e., their preferred substrates, transport mechanisms, metabolic relevance, and disease association for each metabolite class). We will assess missing coverage and propose modifications and additions through a transport module that is functional when combined with Recon 2. This information will be valuable for further refinements. These data will also provide starting points for further experiments by highlighting areas of incomplete knowledge. This review represents the first comprehensive overview of the transporters involved in central metabolism and their transport mechanisms, thus serving as a compendium of metabolite transporters specific for human metabolic reconstructions.

Boronophenylalanine, a boron delivery agent for boron neutron capture therapy, is transported by ATB0,+, LAT1 and LAT2

“…The HPLC‐based uptake assay was applied to screen over human aromatic amino acid transporters to identify BPA transporters. The transporters listed in Table were selected based on the substrate selectivity in which phenylalanine or tyrosine is preferred . The selected amino acid transporters were functionally expressed in Xenopus oocytes (Fig.…”

“…The transporters listed in Table 1 were selected based on the substrate selectivity in which phenylalanine or tyrosine is preferred. (19) The selected amino acid transporters were functionally expressed in Xenopus oocytes (Fig. S1).…”

Systems biology of host–microbe metabolomics

“…Moreover, they can be easily linked to high‐throughput data, such as those obtained through metagenomic or metabolomic analysis . One shortcoming of not accounting for species boundaries is that diffusion (or facilitated transport) of almost any compound in the supra‐organismal metabolic network is assumed, whereas, in reality, only a subset of metabolites can be exchanged between species, and their transport often requires energy, e.g., via ATP‐binding cassette transporters …”

MetaboTools: A Comprehensive Toolbox for Analysis of Genome-Scale Metabolic Models

“…The correct representation of transport mechanisms is important to accurately simulate cellular metabolism; thus, the metabolic reconstructions are continuously extended [7,34,35,44,45]. Hence, before getting started with this step, ensure that the most recent reconstruction version is obtained (e.g., the human metabolic reconstruction is downloadable from https://vmh.uni.lu/).…”

“…The protocol discusses important considerations at individual steps to ensure successfully completion of the workflow (Figure 1). The tips and stipulations are derived from the aforementioned publications but also from our experience with curation and expansion of the human metabolic model using metabolomic data [33][34][35].…”