Journal of advanced research · 2026
N-myristoyltransferase-mediated protein myristoylation: molecular mechanisms, pathological roles, and targeted therapeutic strategies.
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Liu Wenqing, Chen Zhe, Huang Zhen, Chen Linxi
Аннотация
BACKGROUND: Protein N-myristoylation, catalyzed by N-myristoyltransferases (NMT1 and NMT2), is a critical lipid modification conferring membrane-binding and conformational plasticity to target proteins. Historically viewed as a static constitutive membrane anchor, it is now recognized as a dynamic, spatiotemporal molecular rheostat. Emerging discoveries, such as reversible non-canonical lysine myristoylation (Lys-Myr) and myristoylation-driven liquid-liquid phase separation (LLPS), highlight its indispensable role in cellular homeostasis. Consequently, dysregulated myristoylation has emerged as a core pathological driver in diverse diseases, including cancer, neurodegeneration, immune disorders, and infectious diseases.
AIM OF REVIEW: This review critically synthesizes recent breakthroughs in the molecular mechanisms and pathological divergence of N-myristoylation, transitioning from traditional descriptive models to a mechanism-driven framework to bridge fundamental biochemical discoveries with clinical translational applications.
KEY SCIENTIFIC CONCEPTS OF REVIEW: We delineate the transition from classical concepts to novel paradigms, including reversible non-canonical lysine myristoylation (Lys-Myr) and myristoylation-driven liquid-liquid phase separation (LLPS). The review reconstructs disease associations across three core pathological mechanisms: constitutive gain-of-function hyperactivation in oncogenesis (highlighting the NMT1/NMT2 functional paradox), dynamic switch failure in neurodegenerative and immune disorders, and exogenous lipid hijacking in infectious diseases. Finally, we evaluate the therapeutic potential of emerging pan-NMT inhibitors and critically analyze current translational barriers, such as systemic toxicity and methodological limitations in chemical probes. By exploring future therapeutic frontiers, this review provides a comprehensive roadmap for precision therapies targeting the myristoylation network.
AIM OF REVIEW: This review critically synthesizes recent breakthroughs in the molecular mechanisms and pathological divergence of N-myristoylation, transitioning from traditional descriptive models to a mechanism-driven framework to bridge fundamental biochemical discoveries with clinical translational applications.
KEY SCIENTIFIC CONCEPTS OF REVIEW: We delineate the transition from classical concepts to novel paradigms, including reversible non-canonical lysine myristoylation (Lys-Myr) and myristoylation-driven liquid-liquid phase separation (LLPS). The review reconstructs disease associations across three core pathological mechanisms: constitutive gain-of-function hyperactivation in oncogenesis (highlighting the NMT1/NMT2 functional paradox), dynamic switch failure in neurodegenerative and immune disorders, and exogenous lipid hijacking in infectious diseases. Finally, we evaluate the therapeutic potential of emerging pan-NMT inhibitors and critically analyze current translational barriers, such as systemic toxicity and methodological limitations in chemical probes. By exploring future therapeutic frontiers, this review provides a comprehensive roadmap for precision therapies targeting the myristoylation network.