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.

Keywords: cancer; constraint-based modeling; human metabolism; inborn errors of metabolism; metabolic networks and pathways; transport mechanisms.

Figure 1

Overview of transport mechanisms and major transport proteins of the various metabolite classes. (A) The basic modes for metabolite transport across the plasma membrane are shown. Based on the energy association, transport processes can be categorized into active and passive modes based on the energy used. The active mode can be further classified into primary and secondary mechanisms, while the metabolites can also be transported mainly via simple diffusion or facilitated diffusion driven by an increase in entropy. Specialized transport mechanisms (e.g., receptor-mediated endocytosis and tertiary active processes) are not shown. (B–G). Highlights major transport proteins involved in the transport of various substrates belonging to the sugar, amino acid, lipid, nucleoside, vitamin, and other classes mentioned in the text. (H) The present work accesses the coverage and gain in membrane transport systems with reference to the global human metabolic reconstruction, Recon 2 over Recon 1. The review of the relevant scientific literature led to the generation of transport reaction module that contained the proposed additions and modifications, discussed throughout the text. Refer to the text for a further explanation of these transport processes. The color coding for the transport mechanism as shown in (A) has been maintained in the other panels.

Figure 2

Overview of transport reactions captured in the human metabolic reconstructions. The transporter content for the major metabolite classes captured by Recon 2 and Recon 1 are shown and compared. (A) Quantitative assessment of the transport reactions present in Recon 1 (Duarte et al., 2007) and Recon 2 (Thiele et al., 2013). (B) Classification of the transport reactions as per the major class of metabolite transported. (C) Literature support for the transport reactions present in Recon 2. (D) The metabolites were divided into ten metabolite classes and their major transport mechanisms, as captured in Recon 2, are shown. The blood groups comprise the major glycolipids. (E) Comparison of the transport reactions present in Recon 1 and Recon 2. The increased information included and expanded the scope of Recon 2, over Recon 1, resulting in better transporter coverage for the amino acid, carbohydrate, and vitamin classes, while significant work is needed for the lipid class. The following symbols are used: ⋆⋆⋆, good coverage; ⋆⋆, intermediate coverage; ⋆, needs significant effort.