The Human Urate Transportosome: Evolutionary Dynamics, Molecular Mechanisms, and Pharmacogenetic Perspectives.
5 affiliations
- 1N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow 119991, Russia.
- 2Federal State Budgetary Institution "Centre for Strategic Planning and Management of Biomedical Health Risks" of the Federal Medical and Biological Agency, Pogodinskaya Str. 10/1, Moscow 119121, Russia.
- 3JSC "Medsi Group of Companies", Michurinsky Prospekt 56/1, Moscow 119192, Russia.
- 4Department of Medical Genetics and Fundamental Medicine, Bashkir State Medical University, Ufa 450008, Russia.
- 5Department of Propaedeutics of Internal Diseases No. 2, Institute of Clinical Medicine, Pirogov Russian National Research Medical University, Moscow 117513, Russia.
Abstract
Background: The hominoid loss of urate oxidase (uricase) represents a classic evolutionary trade-off, shifting uric acid (UA) from a metabolic waste product to a potent physiological modulator. In modern metabolic environments, however, this adaptation drives hyperuricemia and gout, transforming UA into a primary pathological substrate. Objective: This review aims to dissect the molecular architecture and biophysical networks of the renal and intestinal urate transportosome, delineate the dual intracellular/extracellular "urate paradox," and synthesize genotype-based pharmacogenetic strategies to achieve personalized clinical management. Mechanistic Insights: During the Miocene epoch, inactivating pseudogenization of the UOX gene fixed a novel metabolic phenotype characterized by fructose-driven lipid deposition and enhanced antioxidant protection. Structurally, systemic urate homeostasis is strictly governed by a macromolecular interactome assembled by the four-domain scaffold protein PDZK1 on the epithelial apical membrane. Pathogenic gain-of-function variants in reabsorption facilitators (SLC22A12/URAT1, SLC2A9/GLUT9) or loss-of-function mutations in the efflux pump (ABCG2/BCRP) disrupt this delicate vector kinetics. Within the extracellular space, soluble urate acts as a critical hydrophilic radical scavenger. Paradoxically, upon URAT1/GLUT9-mediated internalization or intracellular supersaturation, intracellular urate triggers a pro-oxidant cascade mediated by NADPH oxidase (NOX4) activation and mitochondrial electron transport chain decoupling. This chronic cellular stress activates downstream p38 MAPK and NF-κB signaling pathways, driving localized endothelial injury and macrovascular inflammation, while crystalline monosodium urate (MSU) orchestrates NLRP3 inflammasome assembly in macrophages. Pharmacogenetic Implications: Striking ethno-geographic heterogeneity dictates immediate clinical stratification. The HLA-B*58:01 allele, an absolute molecular contraindication for allopurinol due to life-threatening severe cutaneous adverse reactions (SCARs), exhibits a critical genetic gradient in northern and eastern Eurasian populations, surging from under 1% in ethnic Caucasians to over 10% in indigenous populations of East/North Asian ancestry. Furthermore, structural defects in ABCG2 (such as the p.Q141K variant) alter the ATP-binding cassette domain, inducing standard allopurinol resistance and elevated statin exposure, which mandates a therapeutic pivot toward selective xanthine oxidase inhibitors (febuxostat) or precision uricosurics (benzbromarone, dotinurad) matched to the patient's interactive network profile. Conclusions: Transitioning from generalized epidemiological guidelines to a comprehensive "transportosome genetic passport" is a fundamental prerequisite for predicting single-nucleotide polymorphism (SNP)-driven therapeutic responses and mitigating visceral complications.
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BibTeX
@article{dzhemileva2026human,
title = {{The Human Urate Transportosome: Evolutionary Dynamics, Molecular Mechanisms, and Pharmacogenetic Perspectives.}},
author = {Lilya U Dzhemileva and Vladimir A D'yakonov and Sergey N Marshala and Elza Khusnutdinova and Andrey A Deviatkin and German A Shipulin},
journal = {Medical sciences (Basel, Switzerland)},
year = {2026},
month = sep,
doi = {10.3390/medsci14060612},
url = {https://europepmc.org/article/MED/42930531},
note = {CC BY},
}
RIS
TY - JOUR
TI - The Human Urate Transportosome: Evolutionary Dynamics, Molecular Mechanisms, and Pharmacogenetic Perspectives.
AU - Lilya U Dzhemileva
AU - Vladimir A D'yakonov
AU - Sergey N Marshala
AU - Elza Khusnutdinova
AU - Andrey A Deviatkin
AU - German A Shipulin
PY - 2026
DA - 2026/09/28
JO - Medical sciences (Basel, Switzerland)
DO - 10.3390/medsci14060612
UR - https://europepmc.org/article/MED/42930531
AB - Background: The hominoid loss of urate oxidase (uricase) represents a classic evolutionary trade-off, shifting uric acid (UA) from a metabolic waste product to a potent physiological modulator. In modern metabolic environments, however, this adaptation drives hyperuricemia and gout, transforming UA into a primary pathological substrate. Objective: This review aims to dissect the molecular architecture and biophysical networks of the renal and intestinal urate transportosome, delineate the dual intracellular/extracellular "urate paradox," and synthesize genotype-based pharmacogenetic strategies to achieve personalized clinical management. Mechanistic Insights: During the Miocene epoch, inactivating pseudogenization of the UOX gene fixed a novel metabolic phenotype characterized by fructose-driven lipid deposition and enhanced antioxidant protection. Structurally, systemic urate homeostasis is strictly governed by a macromolecular interactome assembled by the four-domain scaffold protein PDZK1 on the epithelial apical membrane. Pathogenic gain-of-function variants in reabsorption facilitators (SLC22A12/URAT1, SLC2A9/GLUT9) or loss-of-function mutations in the efflux pump (ABCG2/BCRP) disrupt this delicate vector kinetics. Within the extracellular space, soluble urate acts as a critical hydrophilic radical scavenger. Paradoxically, upon URAT1/GLUT9-mediated internalization or intracellular supersaturation, intracellular urate triggers a pro-oxidant cascade mediated by NADPH oxidase (NOX4) activation and mitochondrial electron transport chain decoupling. This chronic cellular stress activates downstream p38 MAPK and NF-κB signaling pathways, driving localized endothelial injury and macrovascular inflammation, while crystalline monosodium urate (MSU) orchestrates NLRP3 inflammasome assembly in macrophages. Pharmacogenetic Implications: Striking ethno-geographic heterogeneity dictates immediate clinical stratification. The HLA-B*58:01 allele, an absolute molecular contraindication for allopurinol due to life-threatening severe cutaneous adverse reactions (SCARs), exhibits a critical genetic gradient in northern and eastern Eurasian populations, surging from under 1% in ethnic Caucasians to over 10% in indigenous populations of East/North Asian ancestry. Furthermore, structural defects in ABCG2 (such as the p.Q141K variant) alter the ATP-binding cassette domain, inducing standard allopurinol resistance and elevated statin exposure, which mandates a therapeutic pivot toward selective xanthine oxidase inhibitors (febuxostat) or precision uricosurics (benzbromarone, dotinurad) matched to the patient's interactive network profile. Conclusions: Transitioning from generalized epidemiological guidelines to a comprehensive "transportosome genetic passport" is a fundamental prerequisite for predicting single-nucleotide polymorphism (SNP)-driven therapeutic responses and mitigating visceral complications.
SN - 2076-3271
ER -