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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
Pterin metabolites in urine or dried blood spots are measured by high performance liquid chromatography (HPLC) [78–80]. The normal values for biopterin and neopterin in newborns and children are 0.5–3.0 and 1.1–4.0 mmol/mol creatinine, respectively, and the proportion of biopterin is 20–80 percent [81]. In those with defective GTPCH, all pterins are low in blood and urine and the ratio is normal [8, 50]. In patients with 6-PTPS deficiency, the concentrations of biopterin are very low and those of neopterin high. In PCD deficiency, primapterin is formed in the urine, and BH4 is low. In patients with DHPR deficiency, there is a lack of feedback inhibition, and so there may be massive overproduction of urinary pterins, but the level of BH4 is always low. On the other hand, patients with DHPR deficiency have been reported in whom urinary pterin analysis was normal [34, 76, 77], indicating further the importance of enzyme analysis in the diagnosis of this condition. The normal plasma BH4 value is 1.4–3.0; that of blood 2.4–6.0 ng/mL, in CSF 20–60 nmol/L [81].
Homeostasis of Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
TH is subject to both short- and long-term regulation [4]. Short-term regulation occurs rapidly at posttranslational levels and involves feedback inhibition by catecholamines, allosteric regulation, and enzyme phosphorylation. Each of the catecholamines, the end-product of the TH reaction, can inhibit enzyme activity by competing with the pterin cofactor. This results in a reversible enzyme inhibition by converting its active/labile form to an inactive/stable form. In dopaminergic neurons within the brain, end-product inhibition is often associated with the binding of DA to autoreceptors which are localized to various regions of the presynaptic neurons. Such a situation does not generally occur in peripheral DA-producing cells, most of which do not express DA autoreceptors. Allosteric effectors such as heparin, phospholipids, and polyanions do not directly alter the hydroxylation of tyrosine but, rather, increase the affinity of the enzyme for the BH4 cofactor.
Metabolic Diseases
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephanie Grünewald, Alex Broomfield, Callum Wilson
The group of disorders known as the pterin (or more correctly tetrahydrobiopterin disorders) are usually diagnosed following the routine measurement of urine ‘pterins’ that is required in every child who has an elevated phenylalanine level (as seen in PKU) on newborn screening. The key investigation of the other disorders is the measurement of neurotransmitters in the CSF following a set protocol. These conditions can be suspected in patients showing a favourable response to a trial of L-dopa.
Crystal structure of ricin toxin A chain complexed with a highly potent pterin-based small-molecular inhibitor
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Masaru Goto, Natsumi Sakamoto, Shoko Higashi, Rena Kawata, Kazuki Nagatsu, Ryota Saito
For 7PCGY, the pterin ring was bound to the catalytic primary pocket (Figure 3(B)) and interacted with Val81, Gly121, Tyr123, and Arg180 via hydrogen bonds, and with Tyr123 via an aromatic (π-π) interaction (Figure 3(C) and Table 2). These interactions were similarly observed in the X-ray crystallography of the cocrystals of all pterin-based RTA inhibitors with RTA, regardless of inhibitory activity9,10,21–25. The phenyl ring of the tyrosine moiety in 7PCGY interacted with Trp211 in a T-shaped manner (Figure 3(C)), thus, the conformation of Tyr80 was changed from that observed for the inhibitor-free crystal structure (Figure 3(D))26. Together with this movement, the position of Asn122 changed approaching Tyr80 to form a hydrogen bond, as if opening the gate to the secondary pocket. The same conformational changes in Tyr80 and Asn122 were observed with 7PCGF (Figure 3(E)) and 7PCGFF, which exhibited high RTA inhibitory activities10. Furthermore, the 7PCAs that were capable of interacting with the secondary pocket also induced the same rearrangements of Tyr80 and Asn122 upon binding to RTA21,25. Based on these facts, it is strongly suggested that the conformational changes of Tyr80 and Asn122 are crucial for achieving high RTA inhibitory activity.
Clinical, biochemical and molecular spectrum of mild 6-pyruvoyl-tetrahydropterin synthase deficiency and a case report
Published in Fetal and Pediatric Pathology, 2021
Boyan Song, Zhijun Ma, Wei Liu, Lihong Lu, Yongjian Jian, Lu Yu, Zhihui Wan, Xiaofei Yue, Yuanyuan Kong
At 49 days after birth, the results of urine pterin spectrum analysis were as follows: neopterin: 3.44 mmol/molCr (reference range: 1.21–2.92 mmol/molCr), biopterin: 0.21 mmol/molCr (reference range: 0.42–1.92 mmol/molCr), B%: 5.75% (reference range: 19.8%−50.3%; B%=100 × biopterin/(biopterin + neopterin)). DHPR analysis showed that the activity was 1.65 nmol/min 5 mm disc (reference range: 1.02–3.35 nmol/min 5 mm disc), which suggested that the patient had PTS deficiency. In the subsequent three measurements after a low phenylalanine diet, the blood phenylalanine levels fluctuated between 12.1–29.2 mmol/L (Fig. 1), which were below the lower limit of the reference range. Then the low phenylalanine diet was ceased. As the blood phenylalanine level was not high, a BH4 load test was not carried out. The parents refused to provide consent for the cerebrospinal fluid extraction and drug therapy.
The interactions of cephalosporins on polyol pathway enzymes from sheep kidney
Published in Archives of Physiology and Biochemistry, 2018
The polyol pathway is a small, but vital for metabolic system in the organism. The pathway has two enzymes, aldose reductase (AR) and sorbitol dehydrogenase (SDH). This pathway plays a role in converting glucose to fructose via the sugar alcohol intermediate sorbitol using NADPH and NAD+ as cofactors (Mylari et al.2003). Particularly, the activity of the polyol pathway due to the affinity of AR to glucose is increased with high glucose levels in the blood. Thus, sorbitol accumulation occurs in the cell causing osmotic pressure and high oxidative stress and various organ injuries (Kinoshita et al.1962, Greene et al. 1987, Oyama et al.2006). All of excess glucose cannot be converted to the fructose by SDH enzyme in the cell. This case may cause some diabetic complications involving cataract neuropathy, retinopathy and nephropathy (Alım et al.2016). Therefore, determining the effects of drugs or chemicals is very important on polyol enzymes. The studies about both effects of drugs and synthesis of inhibitors have still continued for these enzymes, particularly AR. For example, Sampath et al. (2016) showed that the polyphenols, phloretin, epigallocatechin 3-gallate (EGCG) and [6]-gingerol compounds inhibited the AR enzyme at the low concentration. It was important in terms of inhibitor studies for AR activity. AR is the key enzyme in case of hyperglycaemia, because it is responsible for generating secondary complications during diabetes. In another study, a series of new pterin-7-carboxamides were synthesised as new aldose reductase inhibitors. They evaluated their in vitro inhibitory activities on human AR enzyme. Especially, one of the new pterin-7-carboxamide derivatives has a highest inhibition effects (Saito et al.2016). In our previous study, AR was purified from rat kidney and studied the in vitro inhibition effects of tannic acid, chlorogenic acid, sinapic acid, protocatechuic acid, 4-hydroxybenzoic acid, p-coumaric acid, ferulic acid, vanillic acid, syringic acid, a-resorcylic acid, 3-hydroxybenzoic acid and gallic acid as phenolic acids. From IC50, Ki values were determined that tannic and chlorogenic acids were potential inhibitors against the AR enzyme. We offered that tannic or chlorogenic acid may be a good candidate as a drug for treatment of diabetic complications, after then further biological investigations (Alım et al.2016). Additionally, SDH enzyme was isolated from sheep liver and examined interactions with dacarbazine, methotrexate, epirubicin hydrochloride, calcium folinate, gemcitabine hydrochloride and oxaliplatin as antineoplastic drugs by our laboratory. Dacarbazine was found as the strongest inhibitor compared to the other drugs in the study (Alım and Beydemir 2012).