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Blood clotting is a complex, tightly regulated process involving numerous molecular steps and myriad biomolecules to carry them out, including vitamin K. While the medical field has capitalized on this knowledge to produce medications that toggle up or down vitamin K鈥攖o boost or reduce clotting, respectively鈥攕cientists had not understood how the integral membrane enzyme utilizing vitamin K, vitamin K-dependent gamma carboxylase (VKGC), manages these activities.

Now, in Nature, led by Weikai Li, the Roy and Diana Vagelos Professor of Biochemistry & Molecular Biophysics at WashU Medicine, reveals the molecular details of how VKGC operates. Specifically, the researchers detail how VKGC orchestrates gamma carboxylation, a complex and chemically demanding process essential to proper blood coagulation. When dysfunctional, it can lead to clotting disorders.

First discovered in blood clotting, gamma carboxylation has since been recognized as a central process in many critical aspects of human health, including inflammation, cell death, immune response, vascular integrity, sperm maturation and insulin secretion. Cone snails also use gamma carboxylation to produce a wide array of venomous peptides that target their prey's nerve receptors, offering a rich source of highly specific and fast-acting drug leads. The findings from this study could inform new therapeutic approaches that hinge on this process.

Li's team described a series of cryo-electron microscopy structures of human VKGC in various functional states and in complex with substrate proteins that support hemostasis, alongside biochemical analyses of the multistep catalysis process carried out by VKGC. These findings represent a milestone in understanding how enzymes perform complex reactions with unprecedented chemical demands within a membrane environment.