Complexities of pyridoxine response in PNPO deficiency

Farmania, Rajni; Gupta, Ankit; Ankur, Kumar; Chetry, Sanjeev; Sharma, Suvasini

doi:10.1016/j.ebr.2021.100443

Cited by 5 publications

(2 citation statements)

References 8 publications

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“…On the contrary, with late or no treatment, patients may die or show severe mental handicaps. Some PNPOD seizures were observed to respond to treatment with PLP but not to PN [ 44 ]; nonetheless, some patients’ seizures also responded to PN treatment [ 50 ], and others responded to PN but not to PLP [ 46 , 51 ]. Different susceptibilities of patients to PLP or PN treatments, as well as individuals showing severe to mild phenotypes, are explained because PNPOD can be caused by different point and non-sense mutations as well as deletions/insertions and frame shifts in the HsPNPO gene (see Table 3 in [ 42 ]).…”

Section: The Human Pnpox Enzyme In Diseasementioning

confidence: 99%

Pyridoxal 5′-Phosphate Biosynthesis by Pyridox-(am)-ine 5′-Phosphate Oxidase: Species-Specific Features

Rivero,

Novo,

Medina

2024

IJMS

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Enzymes reliant on pyridoxal 5′-phosphate (PLP), the metabolically active form of vitamin B6, hold significant importance in both biology and medicine. They facilitate various biochemical reactions, particularly in amino acid and neurotransmitter metabolisms. Vitamin B6 is absorbed by organisms in its non-phosphorylated form and phosphorylated within cells via pyridoxal kinase (PLK) and pyridox-(am)-ine 5′-phosphate oxidase (PNPOx). The flavin mononucleotide-dependent PNPOx enzyme converts pyridoxine 5′-phosphate and pyridoxamine 5′-phosphate into PLP. PNPOx is vital for both biosynthesis and salvage pathways in organisms producing B6 vitamers. However, for those depending on vitamin B6 as a nutrient, PNPOx participates only in the salvage pathway. Transferring the PLP produced via PNPOx to client apo-enzymes is indispensable for their catalytic function, proper folding and targeting of specific organelles. PNPOx activity deficiencies due to inborn errors lead to severe neurological pathologies, particularly neonatal epileptic encephalopathy. PNPOx maintains PLP homeostasis through highly regulated mechanisms, including structural alterations throughout the catalytic cycle and allosteric PLP binding, influencing substrate transformation at the active site. Elucidation at the molecular level of the mechanisms underlying PNPOx activity deficiencies is a requirement to develop personalized approaches to treat related disorders. Finally, despite shared features, the few PNPOx enzymes molecularly and functionally studied show species-specific regulatory properties that open the possibility of targeting it in pathogenic organisms.

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Section: The Human Pnpox Enzyme In Diseasementioning

confidence: 99%

Pyridoxal 5′-Phosphate Biosynthesis by Pyridox-(am)-ine 5′-Phosphate Oxidase: Species-Specific Features

Rivero,

Novo,

Medina

2024

IJMS

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“…Similar to PDE-ALDH7A1, PNPO deficiency is characterized by early onset, drug-resistant epileptic encephalopathy [87]. Since the disease gene discovery in 2005 [57], about 90 cases of PNPO deficiency have been reported in the medical literature with a phenotypic spectrum that extends from early postnatal lethality to milder forms with well-controlled seizures and normal neurodevelopmental outcome [88,[97][98][99]. Prematurity is observed in about 50% of the PNPO deficiency cases [88].…”

Section: Clinical Featuresmentioning

confidence: 99%

Vitamin B6 and Related Inborn Errors of Metabolism

Al-Shekaili¹,

Leavitt²

2022

B-Complex Vitamins - Sources, Intakes and Novel Applications

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Vitamin B6 (vitB6) is a generic term that comprises six interconvertible pyridine compounds. These vitB6 compounds (also called vitamers) are pyridoxine (PN), pyridoxamine (PM), pyridoxal (PL) and their 5′-phosphorylated forms pyridoxine 5′-phosphate (PNP), pyridoxamine 5′-phosphate (PMP) and pyridoxal 5′-phosphate (PLP). VitB6 is an essential nutrient for all living organisms, but only microorganisms and plants can carry out de novo synthesis of this vitamin. Other organisms obtain vitB6 from dietary sources and interconvert its different forms according to their needs via a biochemical pathway known as the salvage pathway. PLP is the biologically active form of vitB6 which is important for maintaining the biochemical homeostasis of the body. In the human body, PLP serves as a cofactor for more than 140 enzymatic reactions, mainly associated with synthesis, degradation and interconversion of amino acids and neurotransmitter metabolism. PLP-dependent enzymes are also involved in various physiological processes, including biologically active amine biosynthesis, lipid metabolism, heme synthesis, nucleic acid synthesis, protein and polyamine synthesis and several other metabolic pathways. PLP is an important vitamer for normal brain function since it is required as a coenzyme for the synthesis of several neurotransmitters including D-serine, D-aspartate, L-glutamate, glycine, γ-aminobutyric acid (GABA), serotonin, epinephrine, norepinephrine, histamine and dopamine. Intracellular levels of PLP are tightly regulated and conditions that disrupt this homeostatic regulation can cause disease. In humans, genetic and dietary (intake of high doses of vitB6) conditions leading to increase in PLP levels is known to cause motor and sensory neuropathies. Deficiency of PLP in the cell is also implicated in several diseases, the most notable example of which are the vitB6-dependent epileptic encephalopathies. VitB6-dependent epileptic encephalopathies (B6EEs) are a clinically and genetically heterogeneous group of rare inherited metabolic disorders. These debilitating conditions are characterized by recurrent seizures in the prenatal, neonatal, or postnatal period, which are typically resistant to conventional anticonvulsant treatment but are well-controlled by the administration of PN or PLP. In addition to seizures, children affected with B6EEs may also suffer from developmental and/or intellectual disabilities, along with structural brain abnormalities. Five main types of B6EEs are known to date, these are: PN-dependent epilepsy due to ALDH7A1 (antiquitin) deficiency (PDE-ALDH7A1) (MIM: 266100), hyperprolinemia type 2 (MIM: 239500), PLP-dependent epilepsy due to PNPO deficiency (MIM: 610090), hypophosphatasia (MIM: 241500) and PLPBP deficiency (MIM: 617290). This chapter provides a review of vitB6 and its different vitamers, their absorption and metabolic pathways in the human body, the diverse physiological roles of vitB6, PLP homeostasis and its importance for human health. Finally, the chapter reviews the inherited neurological disorders affecting PLP homeostasis with a special focus on vitB6-dependent epileptic encephalopathies (B6EEs), their different subtypes, the pathophysiological mechanism underlying each type, clinical and biochemical features and current treatment strategies.

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Multiple drugs

2022

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Complexities of pyridoxine response in PNPO deficiency

Cited by 5 publications

References 8 publications

Pyridoxal 5′-Phosphate Biosynthesis by Pyridox-(am)-ine 5′-Phosphate Oxidase: Species-Specific Features

Pyridoxal 5′-Phosphate Biosynthesis by Pyridox-(am)-ine 5′-Phosphate Oxidase: Species-Specific Features

Vitamin B6 and Related Inborn Errors of Metabolism

Multiple drugs

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