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Orphanet Journal of Rare Diseases Jan 2017Aromatic L-amino acid decarboxylase deficiency (AADCD) is a rare, autosomal recessive neurometabolic disorder that leads to a severe combined deficiency of serotonin,... (Review)
Review
Aromatic L-amino acid decarboxylase deficiency (AADCD) is a rare, autosomal recessive neurometabolic disorder that leads to a severe combined deficiency of serotonin, dopamine, norepinephrine and epinephrine. Onset is early in life, and key clinical symptoms are hypotonia, movement disorders (oculogyric crisis, dystonia, and hypokinesia), developmental delay, and autonomic symptoms.In this consensus guideline, representatives of the International Working Group on Neurotransmitter Related Disorders (iNTD) and patient representatives evaluated all available evidence for diagnosis and treatment of AADCD and made recommendations using SIGN and GRADE methodology. In the face of limited definitive evidence, we constructed practical recommendations on clinical diagnosis, laboratory diagnosis, imaging and electroencephalograpy, medical treatments and non-medical treatments. Furthermore, we identified topics for further research. We believe this guideline will improve the care for AADCD patients around the world whilst promoting general awareness of this rare disease.
Topics: Age of Onset; Amino Acid Metabolism, Inborn Errors; Aromatic-L-Amino-Acid Decarboxylases; Cholinergic Antagonists; Dopamine Agonists; Guidelines as Topic; Humans; Monoamine Oxidase Inhibitors; Prolactin; Pyridoxal Phosphate
PubMed: 28100251
DOI: 10.1186/s13023-016-0522-z -
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 -
Current Opinion in Chemical Biology May 2024Pyridoxal phosphate (PLP) is a cofactor that is widely employed in enzymology. This pyridine-containing cofactor can be used for reactions ranging from transaminations... (Review)
Review
Pyridoxal phosphate (PLP) is a cofactor that is widely employed in enzymology. This pyridine-containing cofactor can be used for reactions ranging from transaminations to oxidations. The catalytic versatility can be understood by considering the chemical features of this cofactor. In recent years, exciting new reactions involving PLP have been discovered in natural products biosynthesis, upending our understanding of what this cofactor is capable of. Here we review some of the most exciting PLP-dependent reactions from the last five years.
PubMed: 38815536
DOI: 10.1016/j.cbpa.2024.102472 -
Free Radical Biology & Medicine Nov 2022Selenophosphate synthetases use selenium and ATP to synthesize selenophosphate. This is required for biological utilization of selenium, most notably for the synthesis... (Review)
Review
Selenophosphate synthetases use selenium and ATP to synthesize selenophosphate. This is required for biological utilization of selenium, most notably for the synthesis of the non-canonical amino acid selenocysteine (Sec). Therefore, selenophosphate synthetases underlie all functions of selenoproteins, which include redox homeostasis, protein quality control, hormone regulation, metabolism, and many others. This protein family comprises two groups, SelD/SPS2 and SPS1. The SelD/SPS2 group represent true selenophosphate synthetases, enzymes central to selenium metabolism which are present in all Sec-utilizing organisms across the tree of life. Notably, many SelD/SPS2 proteins contain Sec as catalytic residue in their N-terminal flexible selenium-binding loop, while others replace it with cysteine (Cys). The SPS1 group comprises proteins originated through gene duplications of SelD/SPS2 in metazoa in which the Sec/Cys-dependent catalysis was disrupted. SPS1 proteins do not synthesize selenophosphate and are not required for Sec synthesis. They have essential regulatory functions related to redox homeostasis and pyridoxal phosphate, which affect signaling pathways for growth and differentiation. In this review, we summarize the knowledge about the selenophosphate synthetase family acquired through decades of research, encompassing their structure, mechanism, function, and evolution.
Topics: Adenosine Triphosphate; Cysteine; Hormones; Ligases; Phosphates; Phosphotransferases; Pyridoxal Phosphate; Selenium; Selenium Compounds; Selenocysteine; Selenoproteins
PubMed: 36122644
DOI: 10.1016/j.freeradbiomed.2022.09.007 -
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 -
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 -
RSC Chemical Biology Jun 2024The account attempts to substantiate the hypothesis that, from an evolutionary perspective, the coenzyme couple pyridoxal phosphate and pyridoxamine phosphate preceded... (Review)
Review
The account attempts to substantiate the hypothesis that, from an evolutionary perspective, the coenzyme couple pyridoxal phosphate and pyridoxamine phosphate preceded the coenzyme thiamine pyrophosphate and acted as its less efficient chemical analogue in some form of early metabolism. The analysis combines mechanism-based chemical reactivity with biosynthetic arguments and provides evidence that vestiges of "TPP-like reactivity" are still found for PLP today. From these thoughts, conclusions can be drawn about the key elements of a primordial form of metabolism, which includes the citric acid cycle, amino acid biosynthesis and the pentose phosphate pathway.
PubMed: 38846080
DOI: 10.1039/d4cb00016a -
Frontiers in Cell and Developmental... 2020Peroxisomes are membrane-bound organelles involved in many metabolic pathways and essential for human health. They harbor a large number of enzymes involved in the... (Review)
Review
Peroxisomes are membrane-bound organelles involved in many metabolic pathways and essential for human health. They harbor a large number of enzymes involved in the different pathways, thus requiring transport of substrates, products and cofactors involved across the peroxisomal membrane. Although much progress has been made in understanding the permeability properties of peroxisomes, there are still important gaps in our knowledge about the peroxisomal transport of metabolites and cofactors. In this review, we discuss the different modes of transport of metabolites and essential cofactors, including CoA, NAD, NADP, FAD, FMN, ATP, heme, pyridoxal phosphate, and thiamine pyrophosphate across the peroxisomal membrane. This transport can be mediated by non-selective pore-forming proteins, selective transport proteins, membrane contact sites between organelles, and co-import of cofactors with proteins. We also discuss modes of transport mediated by shuttle systems described for NAD/NADH and NADP/NADPH. We mainly focus on current knowledge on human peroxisomal metabolite and cofactor transport, but also include knowledge from studies in plants, yeast, fruit fly, zebrafish, and mice, which has been exemplary in understanding peroxisomal transport mechanisms in general.
PubMed: 33505966
DOI: 10.3389/fcell.2020.613892