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Patient narratives: Personalized medicine in the field
Published in Priya Hays, Advancing Healthcare Through Personalized Medicine, 2017
Then came another pivotal moment, at a conference where Eric Topol, currently director of the Scripps Translational Science Institute in La Jolla, California, was speaking and talking about sequencing and advances that have been made in the discovery of mutations, which were being found every month. Retta asked researchers at the conference if there was any way “we could pay to have Alexis and Noah’s whole genome sequenced.” After a series of emails through the Beerys’ connections at Life Technologies, of which Invitrogen was a subsidiary, Jim Lupski, from the Baylor College of Medicine, heard of Alexis and Noah’s story through a PBS special and suggested sequencing the Beery twins to see if a genetic mutation responsible for their neurological disorder could be found. Retta emphatically noted that “(sequencing) just required a blood draw.” Three months later, the Beerys met with scientists and physicians at Texas Children’s Hospital. A mutation was found in Alexis and Noah, which they inherited from their parents in the spr gene, or sepiapterin reductase gene. A defect in this gene makes one dopamine and serotonin deficient.
Hyperphenylalaninemia and defective metabolism of tetrahydrobiopterin
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Patients are now being diagnosed earlier because of the initiation of programs in which all hyperphenyalaninemic infants are being investigated for the possibility of defective metabolism of biopterin. However, it has been documented that it is possible to miss a patient with abnormal synthesis of BH4 because early phenylalanine levels may be normal. Therefore, evaluation for a disorder in this pathway should be undertaken in infants with unexplained neurologic disease. Five disorders are considered in this chapter: deficiencies of GTP cyclohydrolase I (GTPCH), recessive as well as dominant forms, 6-pyruvoyltetrahydropterin synthase (PTPS), sepiapterin reductase (SR), dihydropteridine reductase (DHPR), and pterin-4a-carbinolamine dehydratase (PCD) (Figure 16.3). The clinical manifestations of all of them are quite similar, but the carbinolamine hydratase is relatively benign. In addition, variant forms of PTPS and DHPR deficiency exist in which the neurologic signs are either minor or absent. Elevated phenylalanine should initiate investigation in most of these disorders. Sepiapterin reductase, the dominant form of GTPCH I deficiency, and some children with recessively inherited GTPCH deficiency are exceptions in which biopterin is deficient only in the brain [6, 7]. The next step in elucidating a diagnosis is measurement of pterin metabolites in urine or in dry blood spots, and DHPR activity in blood spots. Enzyme activity may be assessed in erythrocytes or cultured fibroblasts. Diagnosis may also be secured by determination of mutations of the relevant gene. Improved prognosis with early therapy makes prompt diagnosis and the timely initiation of therapy important.
The role of biomarkers in stage III non-small cell lung cancer
Published in Expert Review of Respiratory Medicine, 2023
Rafael Rosell, María González-Cao, Masaoki Ito, Mariacarmela Santarpia, Andrés Aguilar, Jordi Codony-Servat
Reactive oxygen species (ROS) production is harmful for polyunsaturated fatty acids (PUFAs) and lipid membranes. Following peroxidation, PUFAs disrupt cellular permeability and membrane function, inducing ferroptosis. In addition to the three previously mentioned resistance mechanisms against ferroptosis (GPX4, FSP1 and DHODH), tetrahydrobiopterin (BH4) has revealed an essential mechanism to compensate from GPX4 inhibition, suggesting that the inhibition of the SLC17A11-GPX4 axis can cause resistance through overexpression of BPH4. Loss of long-chain ACSL4 (Figure 2), which catalyzes the integration of PUFA into membrane phospholipids, improved cell survival when GPX4 is inhibited [59]. It was discovered that under GPX4 inhibition there is an upregulation of enzymes involved in the BH4 pathway, such as GTP cyclohydroxylase−1 (GCH1), 6-pyruvoyltetrahydropterin synthase (PTS) and sepiapterin reductase (SPR). Furthermore, it was identified that dihydrofolate reductase (DHFR) catalyzes the regeneration of BH4 and its inhibition by methotrexate is synergistic with GPX4 blockade [59]. Of utmost relevance, is the fact that sulfasalazine has demonstrated to inhibit sepiapterin reductase (SPR) [60]. Therefore, since sulfasalazine inhibits SLC17A11 (Figures 3, 2), it can presumably be inferred that the use of sulfasalazine could neutralize the counterbalanced rebound effect of BH4 upregulation. Notwithstanding, the action of methotrexate as a potential complementary drug should be kept in mind.
The interplay between aryl hydrocarbon receptor, H. pylori, tryptophan, and arginine in the pathogenesis of gastric cancer
Published in International Reviews of Immunology, 2022
Marzieh Pirzadeh, Nastaran Khalili, Nima Rezaei
BH4 is present in almost every cell and tissue of the body [102] and plays an important role in pain control, cardiovascular function, [103] endothelial dysfunction (thrombosis, arteriosclerosis), immunity, and production of monoamine neurotransmitters [104]. BH4 is synthesized from guanosine triphosphate (GTP). Three enzymes are involved in the production of BH4. Guanosine triphosphate cyclohydrolase (GCH1) is the first and rate-limiting enzyme in the production of BH4, and sepiapterin reductase (SPR) is the last enzyme in BH4 production pathway [105]. Haruki et al. showed that BH4 production is elevated under the influence of pro-inflammatory cytokines and also implicated that xanthurenic acid, a kynurenine pathway metabolite, inhibits SPR enzyme and subsequently attenuates BH4 synthesis [15]. Werner and colleagues also supported the same idea that cytokines such as TNF-α, IL-1, and IFN-ϒ increase the activity of GTP and subsequent production BH4 [106].
Advances in the discovery of new chemotypes through ultra-large library docking
Published in Expert Opinion on Drug Discovery, 2023
Felix Potlitz, Andreas Link, Lukas Schulig
While elevating the sp3-fraction of drug-like molecules has previously been reported to increase aqueous solubility significantly, thus enabling biological screening campaigns to be executed at higher concentrations, there are a plethora of benefits of ‘escaping the flatlands’ in current drug discovery [86,87]. Potential drug candidates exhibiting a higher degree of saturated carbon chains than their phenylic (or aromatic in general) counterparts showed significantly increased metabolic stability and decreased probability of cytochrome p-450 inhibition. Additionally, the replacement inhibited the formation of highly reactive electrophilic benzoquinone species, leading to an overall higher drug-likeness, as reported by Subbaiah et al. [86] . A more three-dimensional approach to the development of novel pharmacophores is enabled by the utilization of spirocyclic structure motifs, such as the spirohydantoin fragment in 1 or the related spiropyrrolidine fragment in 2 the spiranic carbon fixes the carbocycle outside of the plain, therefore conformationally restricting the attached cycle and rotating the associated part of the molecule (Figure 3). Additionally, heterocyclic spirocycles can form hydrogen bonds, allowing interactions with the molecules binding pocket other than lipophilic interactions. Thus the replacement of phenyl residues by (spiro)cycloalkane moieties poses a promising approach to broadening the scope of potential drug-like molecules with improved physicochemical properties. Spirohydantoin-derived drug-like molecules have been investigated for their potential use as antipsychotic and antidepressant agents and their inhibitory effects on certain histone acetyltransferases [88,89]. Rapid assembly of small spirohydantoin-containing libraries is simplified by easy diversification via N-alkylation following the formation of the spirocycle [90]. While 2 has recently been identified as a potential inhibitor of SARS-CoV-2-Mpro, related derivatives of spiropyrrolidine were previously reported to be effective against sepiapterin reductase as well as exhibiting inhibitory effects on cholinesterases [87,91].