Unstructured regions of large enzymatic complexes control the availability of metabolites with signaling functions
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(2020) 18:136
REVIEW
Open Access
Unstructured regions of large enzymatic complexes control the availability of metabolites with signaling functions Ioannis Skalidis1,2 , Christian Tüting1,2
and Panagiotis L. Kastritis1,2,3*
Abstract Metabolites produced via traditional biochemical processes affect intracellular communication, inflammation, and malignancy. Unexpectedly, acetyl-CoA, α-ketoglutarate and palmitic acid, which are chemical species of reactions catalyzed by highly abundant, gigantic enzymatic complexes, dubbed as “metabolons”, have broad “nonmetabolic” signaling functions. Conserved unstructured regions within metabolons determine the yield of these metabolites. Unstructured regions tether functional protein domains, act as spatial constraints to confine constituent enzyme communication, and, in the case of acetyl-CoA production, tend to be regulated by intricate phosphorylation patterns. This review presents the multifaceted roles of these three significant metabolites and describes how their perturbation leads to altered or transformed cellular function. Their dedicated enzymatic systems are then introduced, namely, the pyruvate dehydrogenase (PDH) and oxoglutarate dehydrogenase (OGDH) complexes, and the fatty acid synthase (FAS), with a particular focus on their structural characterization and the localization of unstructured regions. Finally, upstream metabolite regulation, in which spatial occupancy of unstructured regions within dedicated metabolons may affect metabolite availability and subsequently alter cell functions, is discussed. Keywords: Metabolite, Signaling, Acetyl-coenzyme a, α-Ketoglutarate, Palmitic acid, Disorder, Pyruvate dehydrogenase complex, 2-Oxoglutarate dehydrogenase complex, Fatty acid synthase
Background In the second part of the twentieth century, there have been extensive studies that were mainly focused on discovering the molecular mechanisms behind various diseases, and specifically malignancies. Gene knockout, sequencing and, later, −omics methods, as well as network biology, revealed the different underlying pathways that, when perturbed due to various external or internal factors, are the causes of numerous pathological conditions. This collective work led to the creation of a basic * Correspondence: [email protected] 1 Interdisciplinary Research Center HALOmem, Charles Tanford Protein Center, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Straße 3a, Halle/Saale, Germany 2 Institute of Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Straße 3, Halle/Saale, Germany Full list of author information is available at the end of the article
paradigm: a cell will either use an extracellular or intracellular “sensor” to measure changes in the environment and trigger a signaling network. This signal transduction network will propagate via protein-protein interactions, until the signal reaches the nucleus, consequently altering gene expression and triggering a coordinated response to altered conditions, simil
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