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Journal of Inherited Metabolic Disease Jul 2019Vitamin B is present in our diet in many forms, however, only pyridoxal 5'-phosphate (PLP) can function as a cofactor for enzymes. The intestine absorbs... (Review)
Review
Vitamin B is present in our diet in many forms, however, only pyridoxal 5'-phosphate (PLP) can function as a cofactor for enzymes. The intestine absorbs nonphosphorylated B vitamers, which are converted by specific enzymes to the active PLP form. The role of PLP is enabled by its reactive aldehyde group. Pathways reliant on PLP include amino acid and neurotransmitter metabolism, folate and 1-carbon metabolism, protein and polyamine synthesis, carbohydrate and lipid metabolism, mitochondrial function and erythropoiesis. Besides the role of PLP as a cofactor B vitamers also play other cellular roles, for example, as antioxidants, modifying expression and action of steroid hormone receptors, affecting immune function, as chaperones and as an antagonist of Adenosine-5'-triphosphate (ATP) at P2 purinoceptors. Because of the vital role of PLP in neurotransmitter metabolism, particularly synthesis of the inhibitory transmitter γ-aminobutyric acid, it is not surprising that various inborn errors leading to PLP deficiency manifest as B -responsive epilepsy, usually of early onset. This includes pyridox(am)ine phosphate oxidase deficiency (a disorder affecting PLP synthesis and recycling), disorders affecting PLP import into the brain (hypophosphatasia and glycosylphosphatidylinositol anchor synthesis defects), a disorder of an intracellular PLP-binding protein (PLPBP, previously named PROSC) and disorders where metabolites accumulate that inactivate PLP, for example, ALDH7A1 deficiency and hyperprolinaemia type II. Patients with these disorders can show rapid control of seizures in response to either pyridoxine and/or PLP with a lifelong dependency on supraphysiological vitamin B supply. The clinical and biochemical features of disorders leading to B -responsive seizures and the treatment of these disorders are described in this review.
Topics: Epilepsy; Humans; Metabolism, Inborn Errors; Proline; Pyridoxal Phosphate; Pyridoxaminephosphate Oxidase; Pyridoxine; Vitamin B 6; Vitamin B 6 Deficiency
PubMed: 30671974
DOI: 10.1002/jimd.12060 -
Molecular Aspects of Medicine Feb 2017The active form of vitamin B6, pyridoxal 5'-phosphate (PLP), serves as a co-factor in more than 150 enzymatic reactions. Plasma PLP has consistently been shown to be low... (Review)
Review
The active form of vitamin B6, pyridoxal 5'-phosphate (PLP), serves as a co-factor in more than 150 enzymatic reactions. Plasma PLP has consistently been shown to be low in inflammatory conditions; there is a parallel reduction in liver PLP, but minor changes in erythrocyte and muscle PLP and in functional vitamin B6 biomarkers. Plasma PLP also predicts the risk of chronic diseases like cardiovascular disease and some cancers, and is inversely associated with numerous inflammatory markers in clinical and population-based studies. Vitamin B6 intake and supplementation improve some immune functions in vitamin B6-deficient humans and experimental animals. A possible mechanism involved is mobilization of vitamin B6 to the sites of inflammation where it may serve as a co-factor in pathways producing metabolites with immunomodulating effects. Relevant vitamin B6-dependent inflammatory pathways include vitamin B6 catabolism, the kynurenine pathway, sphingosine 1-phosphate metabolism, the transsulfuration pathway, and serine and glycine metabolism.
Topics: Animals; Biomarkers; Humans; Immunity; Inflammation; Pyridoxal Phosphate; Signal Transduction; Vitamin B 6
PubMed: 27593095
DOI: 10.1016/j.mam.2016.08.001 -
Natural Product Reports Nov 2022Covering: up to 2022The report provides a broad approach to deciphering the evolution of coenzyme biosynthetic pathways. Here, these various pathways are analyzed with... (Review)
Review
Covering: up to 2022The report provides a broad approach to deciphering the evolution of coenzyme biosynthetic pathways. Here, these various pathways are analyzed with respect to the coenzymes required for this purpose. Coenzymes whose biosynthesis relies on a large number of coenzyme-mediated reactions probably appeared on the scene at a later stage of biological evolution, whereas the biosyntheses of pyridoxal phosphate (PLP) and nicotinamide (NAD) require little additional coenzymatic support and are therefore most likely very ancient biosynthetic pathways.
Topics: Coenzymes; Pyridoxal Phosphate; Niacinamide
PubMed: 36149232
DOI: 10.1039/d2np00037g -
The FEBS Journal Apr 2020Pyridoxal 5'-phosphate (PLP) is an organic cofactor employed by ~ 4% of enzymes. The structure of the PLP cofactor allows for the stabilization of carbanions through... (Review)
Review
Pyridoxal 5'-phosphate (PLP) is an organic cofactor employed by ~ 4% of enzymes. The structure of the PLP cofactor allows for the stabilization of carbanions through resonance. A small number of PLP-dependent enzymes employ molecular oxygen as a cosubstrate. Here, we review the biological roles and possible mechanisms of these enzymes, and we observe that these enzymes are found in multiple protein families, suggesting that reaction with oxygen might have emerged de novo in several protein families and thus could be directed to emerge again through laboratory evolution experiments.
Topics: Humans; Molecular Structure; Oxygen; Pyridoxal Phosphate
PubMed: 32142210
DOI: 10.1111/febs.15277 -
Biochimica Et Biophysica Acta Sep 2015Pyridoxal-5'-phosphate (PLP) is a versatile cofactor that enzymes use to catalyze a wide variety of reactions of amino acids, including transamination, decarboxylation,... (Review)
Review
Pyridoxal-5'-phosphate (PLP) is a versatile cofactor that enzymes use to catalyze a wide variety of reactions of amino acids, including transamination, decarboxylation, racemization, β- and γ-eliminations and substitutions, retro-aldol and Claisen reactions. These reactions depend on the ability of PLP to stabilize, to a varying degree, α-carbanionic intermediates. Furthermore, oxidative decarboxylations and rearrangements suggest that PLP can stabilize radical intermediates as well. The reaction mechanisms of two PLP-dependent enzymes are discussed, kynureninase and tyrosine phenol-lyase (TPL). Kynureninase catalyzes a retro-Claisen reaction of kynurenine to give anthranilate and alanine. The key step, hydration of the γ-carbonyl, is assisted by acid-base catalysis with the phosphate of the PLP, mediated by a conserved tyrosine, and an oxyanion hole. TPL catalyzes the reversible elimination of phenol, a poor leaving group, from l-tyrosine. In TPL, the Cβ-Cγ bond cleavage is accelerated by ground state strain from the bending of the substrate ring out of the plane with the Cβ-Cγ bond. This article is part of a Special Issue entitled: Cofactor-dependent proteins: evolution, chemical diversity and bio-applications.
Topics: Catalysis; Hydrolases; Pyridoxal Phosphate; Tyrosine Phenol-Lyase
PubMed: 25615531
DOI: 10.1016/j.bbapap.2014.12.028 -
American Journal of TherapeuticsVitamin B6 is essential for life and plays a critical role in many biochemical and physiological processes in the human body. The term B6 collectively refers to 6...
BACKGROUND
Vitamin B6 is essential for life and plays a critical role in many biochemical and physiological processes in the human body. The term B6 collectively refers to 6 water-soluble vitamers, and only the pyridoxal 5'-phosphate (PLP) serves as the biologically active form. A plasma PLP concentration above 30 nmol/L (7.4 μg/L) is indicative of an adequate vitamin B6 status for all age and sex groups. The currently recommended daily allowance of B6 (1.5-2 mg/d) from dietary sources frequently results in inadequate B6 status (<20 nmol/L or 5 μg/L) in many elderly patients and patients with comorbid conditions. PLP-based supplements are preferred and should be administered weekly in low doses (50-100 mg) to maintain a stable serum PLP level between 30 and 60 nmol/L or 7.4 and 15 μg/L.
AREAS OF UNCERTAINTY
It is challenging for physicians to prescribe a safe dose of B6 supplements because of the narrow therapeutic index. The association between elevated levels of pyridoxine and neuropathy is not well established. PLP-based supplements are shown to be least neurotoxic, but further clinical trials are needed to establish the long-term safety in high doses.
DATA SOURCES
PubMed search of randomized control trials and meta-analyses.
THERAPEUTIC OPINION
Plasma B6 levels should be ordered as a part of workup of any unexplained anemia before labeling as "anemia of chronic disease." B6 supplementation is also crucial in the management of chronic Mg deficiency resistant to therapy. When B6 is administered daily in supraphysiologic doses, there is a potential for the development of neurotoxicity (typically at levels >100 nmol/L or 25 μg/L). PLP-based supplements are preferred over pyridoxine supplements because of minimal neurotoxicity observed in neuronal cell viability tests. Since B6 metabolites have a long half-life, weekly administration is preferred over daily use to prevent toxicity.
Topics: Humans; Aged; Pyridoxine; Vitamin B 6; Pyridoxal Phosphate; Dietary Supplements
PubMed: 36608063
DOI: 10.1097/MJT.0000000000001460 -
The Journal of Biological Chemistry Aug 2022Aminotransferases (ATs) are pyridoxal 5'-phosphate-dependent enzymes that catalyze the transamination reactions between amino acid donor and keto acid acceptor... (Review)
Review
Aminotransferases (ATs) are pyridoxal 5'-phosphate-dependent enzymes that catalyze the transamination reactions between amino acid donor and keto acid acceptor substrates. Modern AT enzymes constitute ∼2% of all classified enzymatic activities, play central roles in nitrogen metabolism, and generate multitude of primary and secondary metabolites. ATs likely diverged into four distinct AT classes before the appearance of the last universal common ancestor and further expanded to a large and diverse enzyme family. Although the AT family underwent an extensive functional specialization, many AT enzymes retained considerable substrate promiscuity and multifunctionality because of their inherent mechanistic, structural, and functional constraints. This review summarizes the evolutionary history, diverse metabolic roles, reaction mechanisms, and structure-function relationships of the AT family enzymes, with a special emphasis on their substrate promiscuity and multifunctionality. Comprehensive characterization of AT substrate specificity is still needed to reveal their true metabolic functions in interconnecting various branches of the nitrogen metabolic network in different organisms.
Topics: Biological Evolution; Nitrogen; Pyridoxal Phosphate; Structure-Activity Relationship; Substrate Specificity; Transaminases
PubMed: 35697072
DOI: 10.1016/j.jbc.2022.102122 -
Amino Acids Feb 2018Pyridoxal 5'-phosphate (PLP)-dependent enzymes catalyze a wide range of reactions of amino acids and amines, with the exception of glycogen phosphorylase which exhibits... (Review)
Review
Pyridoxal 5'-phosphate (PLP)-dependent enzymes catalyze a wide range of reactions of amino acids and amines, with the exception of glycogen phosphorylase which exhibits peculiar both substrate preference and chemical mechanism. They represent about 4% of the gene products in eukaryotic cells. Although structure-function investigations regarding these enzymes are copious, their regulation by post-translational modifications is largely unknown. Protein phosphorylation is the most common post-translational modification fundamental in mediating diverse cellular functions. This review aims at summarizing the current knowledge on regulation of PLP enzymes by phosphorylation. Starting from the paradigmatic PLP-dependent glycogen phosphorylase, the first phosphoprotein discovered, we collect data in literature regarding functional phosphorylation events of eleven PLP enzymes belonging to different fold types and discuss the impact of the modification in affecting their activity and localization as well as the implications on the pathogenesis of diseases in which many of these enzymes are involved. The pivotal question is to correlate the structural consequences of phosphorylation among PLP enzymes of different folds with the functional modifications exerted in terms of activity or conformational changes or others. Although the literature shows that the phosphorylation of PLP enzymes plays important roles in mediating diverse cellular functions, our recapitulation of clue findings in the field makes clear that there is still much to be learnt. Besides mass spectrometry-based proteomic analyses, further biochemical and structural studies on purified native proteins are imperative to fully understand and predict how phosphorylation regulates PLP enzymes and to find the relationship between addition of a phosphate moiety and physiological response.
Topics: Amino Acids; Enzymes; Glycogen Phosphorylase; Humans; Models, Molecular; Phosphates; Phosphorylation; Protein Folding; Pyridoxal Phosphate; Structure-Activity Relationship
PubMed: 29204749
DOI: 10.1007/s00726-017-2521-3 -
Journal of the American Chemical Society May 2024Pyridoxal 5'-phosphate (PLP)-dependent enzymes are the most versatile biocatalysts for synthesizing nonproteinogenic amino acids. α,α-Disubstituted quaternary amino...
Pyridoxal 5'-phosphate (PLP)-dependent enzymes are the most versatile biocatalysts for synthesizing nonproteinogenic amino acids. α,α-Disubstituted quaternary amino acids, such as 1-aminocyclopentane-1-carboxylic acid (cycloleucine), are useful building blocks for pharmaceuticals. In this study, starting with the biosynthesis of fusarilin A, we discovered a family of PLP-dependent enzymes that can facilitate tandem carbon-carbon forming steps to catalyze an overall [3 + 2]-annulation. In the first step, the cycloleucine synthases use SAM as the latent electrophile and an in situ-generated enamine as the nucleophile for γ-substitution. Whereas previously characterized γ-replacement enzymes protonate the resulting α-carbon and release the acyclic amino acid, cycloleucine synthases can catalyze an additional, intramolecular aldol or Mannich reaction with the nucleophilic α-carbon to form the substituted cyclopentane. Overall, the net [3 + 2]-annulation reaction can lead to 2-hydroxy or 2-aminocycloleucine products. These studies further expand the biocatalytic scope of PLP-dependent enzymes.
Topics: Pyridoxal Phosphate; Biocatalysis; Molecular Structure; Cyclopentanes
PubMed: 38743881
DOI: 10.1021/jacs.4c02142 -
Heart (British Cardiac Society) Nov 2019Gadolinium-based contrast media are widely used in cardiovascular MRI to identify and to highlight the intravascular and extracellular space. After gadolinium, manganese... (Review)
Review
Gadolinium-based contrast media are widely used in cardiovascular MRI to identify and to highlight the intravascular and extracellular space. After gadolinium, manganese has the second highest paramagnetic moment and was one of the first MRI contrast agents assessed in humans. Over the last 50 years, manganese-enhanced MRI (MEMRI) has emerged as a complementary approach enabling intracellular myocardial contrast imaging that can identify functional myocardium through its ability to act as a calcium analogue. Early progress was limited by its potential to cause myocardial depression. To overcome this problem, two clinical formulations of manganese were developed using either chelation (manganese dipyridoxyl diphosphate) or coadministration with a calcium compound (EVP1001-1, Eagle Vision Pharmaceuticals). Preclinical studies have demonstrated the efficacy of MEMRI in quantifying myocardial infarction and detecting myocardial viability as well as tracking altered contractility and calcium handling in cardiomyopathy. Recent clinical data suggest that MEMRI has exciting potential in the quantification of myocardial viability in ischaemic cardiomyopathy, the early detection of abnormalities in myocardial calcium handling, and ultimately, in the development of novel therapies for myocardial infarction or heart failure by actively quantifying viable myocardium. The stage is now set for wider clinical translational study of this novel and promising non-invasive imaging modality.
Topics: Animals; Calcium Signaling; Cardiomyopathies; Contrast Media; Edetic Acid; Humans; Magnetic Resonance Imaging; Manganese; Myocardium; Predictive Value of Tests; Prognosis; Pyridoxal Phosphate; Tissue Survival
PubMed: 31337670
DOI: 10.1136/heartjnl-2019-315227