Abstract
Genome-scale metabolic models (GEMs) are powerful tools for understanding metabolism from a systems-level perspective. However, GEMs in their most basic form fail to account for cellular regulation. A diverse set of mechanisms regulate cellular metabolism, enabling organisms to respond to a wide range of conditions. This limitation of GEMs has prompted the development of new methods to integrate regulatory mechanisms, thereby enhancing the predictive capabilities and broadening the scope of GEMs. Here, we cover integrative models encompassing six types of regulatory mechanisms: transcriptional regulatory networks (TRNs), post-translational modifications (PTMs), epigenetics, protein–protein interactions and protein stability (PPIs/PS), allostery, and signaling networks. We discuss 22 integrative GEM modeling methods and how these have been used to simulate metabolic regulation during normal and pathological conditions. While these advances have been remarkable, there remains a need for comprehensive and widespread integration of regulatory constraints into GEMs. We conclude by discussing challenges in constructing GEMs with regulation and highlight areas that need to be addressed for the successful modeling of metabolic regulation. Next-generation integrative GEMs that incorporate multiple regulatory mechanisms and their crosstalk will be invaluable for discovering cell-type and disease-specific metabolic control mechanisms.
Highlights
Cellular metabolism is a fundamental biological process used by all living organisms to generate and expend energy for growth [1]
We present and discuss 22 methods that have mechanistically integrated regulatory information relevant to the six mechanisms listed above into genome-scale metabolic models (GEMs) (Table 1)
The authors developed a new constraint-based modeling method, called allosteric regulation flux balance analysis (FBA), which was designed to incorporate allosteric regulation when solving for flux predictions
Summary
Cellular metabolism is a fundamental biological process used by all living organisms to generate and expend energy for growth [1]. Transcriptional regulation dictates enzyme abundance via changes in gene expression in response to nutrient availability. Since the scope and capabilities of GEMs are a function of how accurately they emulate metabolism, a frontier of metabolic modeling is developing ways to integrate regulatory aspects into GEMs. In this review, we cover six different types: transcriptional regulatory networks (TRNs), post-translational modifications (PTMs), epigenetics, protein–protein interactions and protein stability (PPIs/PS), allostery, and signaling (Figure 1). We cover six different types: transcriptional regulatory networks (TRNs), post-translational modifications (PTMs), epigenetics, protein–protein interactions and protein stability (PPIs/PS), allostery, and signaling (Figure 1) While this enumeration of regulatory mechanisms is not exhaustive, these six mechanisms represent major ways through which cellular regulation affects metabolism.
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