Abstract
Metabolism is the sum of the life-giving chemical processes that occur within a cell. Proper regulation of these processes is essential for all organisms to thrive and prosper. When external factors are too extreme, or if internal regulation is corrupted through genetic or epigenetic changes, metabolic homeostasis is no longer achievable and diseases such as metabolic syndrome or cancer, aging, and, ultimately, death ensue. Metabolic reactions are catalyzed by proteins, and the in vitro kinetic properties of these enzymes have been studied by biochemists for many decades. These efforts led to the appreciation that enzyme activities can be acutely regulated and that this regulation is critical to metabolic homeostasis. Regulation can be mediated through allosteric interactions with metabolites themselves or via post-translational modifications triggered by intracellular signal transduction pathways. More recently, enzyme regulation has attracted the attention of cell biologists who noticed that change in growth conditions often triggers the condensation of diffusely localized enzymes into one or more discrete foci, easily visible by light microscopy. This reorganization from a soluble to a condensed state is best described as a phase separation. As summarized in this review, stimulus-induced phase separation has now been observed for dozens of enzymes suggesting that this could represent a widespread mode of activity regulation, rather than, or in addition to, a storage form of temporarily superfluous enzymes. Building on our recent structure determination of TOROIDs (TORc1 Organized in Inhibited Domain), the condensate formed by the protein kinase Target Of Rapamycin Complex 1 (TORC1), we will highlight that the molecular organization of enzyme condensates can vary dramatically and that future work aimed at the structural characterization of enzyme condensates will be critical to understand how phase separation regulates enzyme activity and consequently metabolic homeostasis. This information may ultimately facilitate the design of strategies to target the assembly or disassembly of specific enzymes condensates as a therapeutic approach to restore metabolic homeostasis in certain diseases.
Highlights
Proper regulation of these processes is essential for all organisms to thrive and prosper
PKM2, encoded by the PKM locus, and PKR and PKL, encoded by the PKLR locus. Expression of these isoforms is regulated both transcriptionally and post-transcriptionally through alternative splicing and correlates with metabolic demand of the tissue; PKM2 is expressed in proliferating and tumor cells while PKM1 is found in tissues with high catabolic demand such as heart and brain as well as some tumors [4]
As evidenced in bacteria [6], this regulation plays an important role in controlling glycolytic flux; FBP accumulates when glucose is plentiful and signals a sufficiency, or full reservoir, of upper-glycolysis metabolites that, by stimulation of pyruvate kinase, can be siphoned off through lower glycolysis
Summary
Homeostatic control over metabolism requires intricate regulation of metabolite flux. The best understood allosteric regulator of pyruvate kinase is the glycolytic metabolite fructose-1,6-bisphosphate (FBP) It activates both PKM2 and Cdc by stabilizing their conversion from modestly active dimers to robustly active tetramers. As evidenced in bacteria [6], this regulation plays an important role in controlling glycolytic flux; FBP accumulates when glucose is plentiful and signals a sufficiency, or full reservoir, of upper-glycolysis metabolites that, by stimulation of pyruvate kinase, can be siphoned off through lower glycolysis. Phosphorylation of several residues in a low-complexity region (LCR), by an unknown kinase, was recently suggested to alter Cdc activity through a fourth mode of regulation—phase separation into a molecular condensate [11]. The LCR is exposed and this is necessary and sufficient to drive condensation (phase separation) of Cdc into foci. Elucidating the structures of these particular condensates provides detailed molecular insight into how phase separation can regulate enzymatic activity and may guide future efforts into the design of approaches to manipulate this mode of regulation for therapeutic gain
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