RBC-GEM: a Knowledge Base for Systems Biology of Human Red Blood Cell Metabolism

Advancements with cost-effective, high-throughput omics technologies have had a transformative effect on both fundamental and translational research in the medical sciences. These advancements have facilitated a departure from the traditional view of human red blood cells (RBCs) as mere carriers of hemoglobin, devoid of significant biological complexity. Over the past decade, proteomic analyses have identified a growing number of different proteins present within RBCs, enabling systems biology analysis of their physiological functions. Here, we introduce RBC-GEM, the most extensive and meticulously curated metabolic reconstruction of a specific human cell type to-date. It was developed through meta-analysis of proteomic data from 28 studies published over the past two decades resulting in a RBC proteome composed of more than 4,600 distinct proteins. Through workflow-guided manual curation, we have compiled the metabolic reactions carried out by this proteome. RBC-GEM is hosted on a version-controlled GitHub repository, ensuring adherence to the standardized protocols for metabolic reconstruction quality control and data stewardship principles. This reconstruction of the RBC metabolic network is a knowledge base consisting of 718 genes encoding proteins acting on 1,590 unique metabolites through 2,554 biochemical reactions: a 700% size expansion over its predecessor. This reconstruction as an up-to-date curated knowledge base can be used for contextualization of data and for the construction of a computational whole-cell model of a human RBC. Author SummaryHuman red blood cells (RBCs) have been studied for decades because of their unique physiology, essential oxygen delivery functions, and general accessibility. RBCs are the simplest yet most numerous of human cell types due to the loss of cellular organelles during their development process. This process has evolved to maximize hemoglobin content per cell to facilitate RBCs main function in gas transport. RBCs are integral to a variety of medical applications, such as blood storage for transfusion. Recent advancements in high-throughput data collection have greatly expanded our understanding of RBC metabolism, highlighting important roles and functions for RBCs in maintaining homeostasis in the organism in addition to oxygen transport. Here we provide a knowledge base for the human RBC as a genome-scale metabolic reconstruction. Our results highlight the complexity of RBC metabolism, supported by recent advancements in high-throughput data collection methods for detecting low-abundance proteins in RBCs. We make knowledge about the RBC findable, accessible, interoperable, and reusable (FAIR). As RBC research is likely to see many translational medical advancements, a knowledge base for the contextualization of RBC data will serve as an essential resource for further research and medical application development.