GTP-cyclohydrolase deficiency induced peripheral and deep microcirculation dysfunction with age

Simonet, Serge; Gosgnach, Willy; Billou, Lucie; Lucats, Laurence; Royere, Emilie; Crespo, Christine; Lapret, Isabelle; Ragonnet, Lea; Moreau, Kévin; Vayssettes-Courchay, Christine; Berson, Pascal; Bourguignon, Marie-Pierre

doi:10.1016/j.mvr.2020.104078

Cited by 3 publications

(3 citation statements)

References 42 publications

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“…Both, absence or lack of BH 4 and increasing BH 2 have been shown to codetermine uncoupling of endothelial NOS, resulting in generation of oxygen radicals instead of the antiatherogenic nitric oxide even in the absence of exogenous oxidative stress 34 . In addition, BH 4 is required for regulation of vascular tone and blood pressure as demonstrated in a mouse model, 35 with microvasculature being apparently predominantly affected 36 . Interestingly, calcification of the walls of small, medium, and large arteries and veins as well as calcification in perivascular spaces has been found on histopathology in two patients with DHPRD 37,38 .…”

Section: Discussionmentioning

confidence: 99%

“…34 In addition, BH 4 is required for regulation of vascular tone and blood pressure as demonstrated in a mouse model, 35 with microvasculature being apparently predominantly affected. 36 Interestingly, calcification of the walls of small, medium, and large arteries and veins as well as calcification in perivascular spaces has been found on histopathology in two patients with DHPRD. 37,38 Thus, intermittently hampered vascular function and/or premature vessel degeneration due to increased oxygen radicals might exacerbate hypotensive episodes.…”

Section: Injury In Cerebral and Cerebellar Watershed Areasmentioning

confidence: 95%

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Brain MR patterns in inherited disorders of monoamine neurotransmitters: An analysis of 70 patients

Hübschmann

Mohr

Friedman

et al. 2021

J of Inher Metab Disea

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Inherited monoamine neurotransmitter disorders (iMNDs) are rare disorders with clinical manifestations ranging from mild infantile hypotonia, movement disorders to early infantile severe encephalopathy. Neuroimaging has been reported as non-specific. We systematically analyzed brain MRIs in order to characterize and better understand neuroimaging changes and to re-evaluate the diagnostic role of brain MRI in iMNDs. 81 MRIs of 70 patients (0.1-52.9 years, 39 patients with tetrahydrobiopterin deficiencies, 31 with primary disorders of monoamine metabolism) were retrospectively analyzed and clinical records reviewed. 33/70 patients had MRI changes, most commonly atrophy (n = 24). Eight patients, six with dihydropteridine reductase deficiency (DHPR), had a common pattern of bilateral parieto-occipital and to a lesser extent frontal and/or cerebellar changes in arterial watershed zones. Two patients imaged after acute severe encephalopathy had signs of profound hypoxic-ischemic injury and a combination of deep gray matter and watershed injury (aromatic L-amino acid decarboxylase (AADCD), tyrosine hydroxylase deficiency (THD)). Four patients had myelination delay (AADCD; THD); two had changes characteristic of postinfantile onset neuronal disease (AADCD, monoamine oxidase A deficiency), and nine T2-hyperintensity of central tegmental tracts. iMNDs are associated with MRI patterns consistent with chronic effects of a neuronal disorder and signs of repetitive injury to cerebral and cerebellar watershed areas, in particular in DHPRD. These will be helpful in the (neuroradiological) differential diagnosis of children with unknown disorders and monitoring of iMNDs. We hypothesize that deficiency of catecholamines and/or tetrahydrobiopterin increase the incidence of and the CNS susceptibility to vascular dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: Injury In Cerebral and Cerebellar Watershed Areasmentioning

confidence: 95%

Brain MR patterns in inherited disorders of monoamine neurotransmitters: An analysis of 70 patients

Hübschmann

Mohr

Friedman

et al. 2021

J of Inher Metab Disea

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“…BH4 plays an empirical role in maintaining cardiovascular, inflammatory, and neurovascular homeostasis. − Additionally, mutations in the gene encoding the GCH1 enzyme result in rare human genetic disorders such as malignant hyperphenylalaninemia, dopamine responsive dystonia, and Parkinson’s disease . Therefore, GCH1 stands as an attractive drug target for developing novel drugs directed against several human diseases, including rare hereditary disorders, pulmonary hypertension, atherosclerosis, diabetes mellitus, Alzheimer’s disease, depression, and neuropathic pain. ,,− …”

Section: Introductionmentioning

confidence: 99%

GTP Cyclohydrolase I as a Potential Drug Target: New Insights into Its Allosteric Modulation via Normal Mode Analysis

Khairallah

Ross

Bishop

2021

J. Chem. Inf. Model.

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Guanosine triphosphate (GTP) cyclohydrolase I (GCH1) catalyzes the conversion of GTP into dihydroneopterin triphosphate (DHNP). DHNP is the first intermediate of the folate de novo biosynthesis pathway in prokaryotic and lower eukaryotic microorganisms and the tetrahydrobiopterin (BH4) biosynthesis pathway in higher eukaryotes. The de novo folate biosynthesis provides essential cofactors for DNA replication, cell division, and synthesis of key amino acids in rapidly replicating pathogen cells, such as Plasmodium falciparum (P. falciparum), a causative agent of malaria. In eukaryotes, the product of the BH4 biosynthesis pathway is essential for the production of nitric oxide and several neurotransmitter precursors. An increased copy number of the malaria parasite P. falciparum GCH1 gene has been reported to influence antimalarial antifolate drug resistance evolution, whereas mutations in the human GCH1 are associated with neuropathic and inflammatory pain disorders. Thus, GCH1 stands as an important and attractive drug target for developing therapeutics. The GCH1 intrinsic dynamics that modulate its activity remains unclear, and key sites that exert allosteric effects across the structure are yet to be elucidated. This study employed the anisotropic network model to analyze the intrinsic motions of the GCH1 structure alone and in complex with its regulatory partner protein. We showed that the GCH1 tunnel-gating mechanism is regulated by a global shear motion and an outward expansion of the central five-helix bundle. We further identified hotspot residues within sites of structural significance for the GCH1 intrinsic allosteric modulation. The obtained results can provide a solid starting point to design novel antineuropathic treatments for humans and novel antimalarial drugs against the malaria parasite P. falciparum GCH1 enzyme.

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Aging increases circulating BH2 without modifying BH4 levels and impairs peripheral vascular function in healthy adults

Bouly

Bourguignon

Roesch

et al. 2021

Translational Research

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GTP-cyclohydrolase deficiency induced peripheral and deep microcirculation dysfunction with age

Cited by 3 publications

References 42 publications

Brain MR patterns in inherited disorders of monoamine neurotransmitters: An analysis of 70 patients

Brain MR patterns in inherited disorders of monoamine neurotransmitters: An analysis of 70 patients

GTP Cyclohydrolase I as a Potential Drug Target: New Insights into Its Allosteric Modulation via Normal Mode Analysis

Aging increases circulating BH2 without modifying BH4 levels and impairs peripheral vascular function in healthy adults

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