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Biochimica Et Biophysica Acta.... Jan 2021The molybdenum cofactor (Moco) represents an ancient metal‑sulfur cofactor, which participates as catalyst in carbon, nitrogen and sulfur cycles, both on individual... (Review)
Review
The molybdenum cofactor (Moco) represents an ancient metal‑sulfur cofactor, which participates as catalyst in carbon, nitrogen and sulfur cycles, both on individual and global scale. Given the diversity of biological processes dependent on Moco and their evolutionary age, Moco is traced back to the last universal common ancestor (LUCA), while Moco biosynthetic genes underwent significant changes through evolution and acquired additional functions. In this review, focused on eukaryotic Moco biology, we elucidate the benefits of gene fusions on Moco biosynthesis and beyond. While originally the gene fusions were driven by biosynthetic advantages such as coordinated expression of functionally related proteins and product/substrate channeling, they also served as origin for the development of novel functions. Today, Moco biosynthetic genes are involved in a multitude of cellular processes and loss of the according gene products result in severe disorders, both related to Moco biosynthesis and secondary enzyme functions.
Topics: Coenzymes; Eukaryota; Gene Fusion; Humans; Metalloproteins; Molybdenum; Molybdenum Cofactors; Pteridines; Substrate Specificity
PubMed: 33017596
DOI: 10.1016/j.bbamcr.2020.118883 -
Nitric Oxide : Biology and Chemistry Apr 2014It is now accepted that the anion nitrite, once considered an inert oxidation product of nitric oxide (NO), contributes to hypoxic vasodilation, physiological blood... (Review)
Review
It is now accepted that the anion nitrite, once considered an inert oxidation product of nitric oxide (NO), contributes to hypoxic vasodilation, physiological blood pressure control, and redox signaling. As such, its application in therapeutics is being actively tested in pre-clinical models and in human phase I-II clinical trials. Major pathways for nitrite bioactivation involve its reduction to NO by members of the hemoglobin or molybdopterin family of proteins, or catalyzed dysproportionation. These conversions occur preferentially under hypoxic and acidic conditions. A number of enzymatic systems reduce nitrite to NO and their activity and importance are defined by oxygen tension, specific organ system and allosteric and redox effectors. In this work, we review different proposed mechanisms of nitrite bioactivation, focusing on analysis of kinetics and experimental evidence for the relevance of each mechanism under different conditions.
Topics: Animals; Coenzymes; Hemeproteins; Humans; Kinetics; Metalloproteins; Molybdenum Cofactors; Nitrites; Pteridines
PubMed: 24315961
DOI: 10.1016/j.niox.2013.11.002 -
Molecules (Basel, Switzerland) Jul 2023Mo/W-containing formate dehydrogenases (FDH) catalyzes the reversible oxidation of formate to carbon dioxide at their molybdenum or tungsten active sites. The... (Review)
Review
Mo/W-containing formate dehydrogenases (FDH) catalyzes the reversible oxidation of formate to carbon dioxide at their molybdenum or tungsten active sites. The metal-containing FDHs are members of the dimethylsulfoxide reductase family of mononuclear molybdenum cofactor (Moco)- or tungsten cofactor (Wco)-containing enzymes. In these enzymes, the active site in the oxidized state comprises a Mo or W atom present in the bis-Moco, which is coordinated by the two dithiolene groups from the two MGD moieties, a protein-derived SeCys or Cys, and a sixth ligand that is now accepted as being a sulfido group. SeCys-containing enzymes have a generally higher turnover number than Cys-containing enzymes. The analogous chemical properties of W and Mo, the similar active sites of W- and Mo-containing enzymes, and the fact that W can replace Mo in some enzymes have led to the conclusion that Mo- and W-containing FDHs have the same reaction mechanism. Details of the catalytic mechanism of metal-containing formate dehydrogenases are still not completely understood and have been discussed here.
Topics: Formate Dehydrogenases; Oxidation-Reduction; Metalloproteins; Molybdenum; Catalytic Domain; Pteridines; Coenzymes
PubMed: 37513211
DOI: 10.3390/molecules28145338 -
International Journal of Molecular... Jul 2019Dimethyl sulfoxide reductases (DMSO) are molybdoenzymes widespread in all domains of life. They catalyse not only redox reactions, but also hydroxylation/hydration and... (Review)
Review
Dimethyl sulfoxide reductases (DMSO) are molybdoenzymes widespread in all domains of life. They catalyse not only redox reactions, but also hydroxylation/hydration and oxygen transfer processes. Although literature on DMSO is abundant, the biological significance of these enzymes in anaerobic respiration and the molecular mechanisms beyond the expression of genes coding for them are still scarce. In this review, a deep revision of the literature reported on DMSO as well as the use of bioinformatics tools and free software has been developed in order to highlight the relevance of DMSO reductases on anaerobic processes connected to different biogeochemical cycles. Special emphasis has been addressed to DMSO from extremophilic organisms and their role in nitrogen cycle. Besides, an updated overview of phylogeny of DMSOs as well as potential applications of some DMSO reductases on bioremediation approaches are also described.
Topics: Coenzymes; Extremophiles; Iron-Sulfur Proteins; Isoenzymes; Metabolic Networks and Pathways; Metalloproteins; Molybdenum; Molybdenum Cofactors; Multigene Family; Nitrogen Cycle; Oxidation-Reduction; Oxidoreductases; Phylogeny; Pteridines; Structure-Activity Relationship; Tungsten
PubMed: 31288391
DOI: 10.3390/ijms20133349 -
The Journal of Biological Chemistry May 2013The transition element molybdenum needs to be complexed by a special cofactor to gain catalytic activity. Molybdenum is bound to a unique pterin, thus forming the... (Review)
Review
The transition element molybdenum needs to be complexed by a special cofactor to gain catalytic activity. Molybdenum is bound to a unique pterin, thus forming the molybdenum cofactor (Moco), which, in different variants, is the active compound at the catalytic site of all molybdenum-containing enzymes in nature, except bacterial molybdenum nitrogenase. The biosynthesis of Moco involves the complex interaction of six proteins and is a process of four steps, which also require iron, ATP, and copper. After its synthesis, Moco is distributed, involving Moco-binding proteins. A deficiency in the biosynthesis of Moco has lethal consequences for the respective organisms.
Topics: Animals; Biosynthetic Pathways; Coenzymes; Humans; Metalloexopeptidases; Metalloproteins; Molybdenum; Molybdenum Cofactors; Organophosphorus Compounds; Pteridines; Pterins
PubMed: 23539623
DOI: 10.1074/jbc.R113.455311 -
In Vivo (Athens, Greece) 2022Indoxyl sulfate is a metabolite of tryptophan and its urinary level reflects the status of bacterial flora in the intestine. Indoxyl sulfate possesses prooxidant...
BACKGROUND/AIM
Indoxyl sulfate is a metabolite of tryptophan and its urinary level reflects the status of bacterial flora in the intestine. Indoxyl sulfate possesses prooxidant properties and is implicated in various diseases including chronic kidney disease and cardiovascular diseases. However, the relation of urinary indoxyl sulfate to oxidative stress is not known.
PATIENTS AND METHODS
The association of urinary indoxyl sulfate levels with urinary levels of oxidative stress markers, 15-isoprostane F and pteridine derivatives, was investigated in 255 patients with type 2 diabetes. Indoxyl sulfate and pteridine derivatives were measured by using spectrofluorometry.
RESULTS
Urinary levels of indoxyl sulfate, pteridines, and 15-isoprostane F showed a normal distribution after logarithmic transformation but not before it, and they were thus used for parametric analysis after logarithmic transformation. Urinary indoxyl sulfate levels were significantly correlated (p<0.01) with urinary 15-isoprostane F and pteridine levels [Pearson's correlation coefficients: 0.503 (15-isoprostane F) and 0.562 (pteridines)]. These associations were also found in multivariable analysis after adjusting for age, sex, insulin therapy for diabetes, body mass index, mean arterial pressure, hemoglobin A1, estimated glomerular filtration rate, urinary albumin, and histories of smoking and alcohol drinking.
CONCLUSION
Urinary indoxyl sulfate levels showed associations with urinary levels of oxidative stress markers, and the associations were independent of age, sex, insulin therapy for diabetes, body mass index, blood pressure, glycemic status, renal function, smoking, and alcohol drinking. Indoxyl sulfate appears to be an important determinant of redox balance in patients with diabetes.
Topics: Biomarkers; Diabetes Mellitus, Type 2; Humans; Indican; Insulins; Isoprostanes; Oxidative Stress; Pteridines
PubMed: 35738626
DOI: 10.21873/invivo.12893 -
International Journal of Molecular... Dec 2022Pterins are an inseparable part of living organisms. Pterins participate in metabolic reactions mostly as tetrahydropterins. Dihydropterins are usually intermediates of... (Review)
Review
Pterins are an inseparable part of living organisms. Pterins participate in metabolic reactions mostly as tetrahydropterins. Dihydropterins are usually intermediates of these reactions, whereas oxidized pterins can be biomarkers of diseases. In this review, we analyze the available data on the quantum chemistry of unconjugated pterins as well as their photonics. This gives a comprehensive overview about the electronic structure of pterins and offers some benefits for biomedicine applications: (1) one can affect the enzymatic reactions of aromatic amino acid hydroxylases, NO synthases, and alkylglycerol monooxygenase through UV irradiation of Hpterins since UV provokes electron donor reactions of Hpterins; (2) the emission properties of Hpterins and oxidized pterins can be used in fluorescence diagnostics; (3) two-photon absorption (TPA) should be used in such pterin-related infrared therapy because single-photon absorption in the UV range is inefficient and scatters in vivo; (4) one can affect pathogen organisms through TPA excitation of Hpterin cofactors, such as the molybdenum cofactor, leading to its detachment from proteins and subsequent oxidation; (5) metal nanostructures can be used for the UV-vis, fluorescence, and Raman spectroscopy detection of pterin biomarkers. Therefore, we investigated both the biochemistry and physical chemistry of pterins and suggested some potential prospects for pterin-related biomedicine.
Topics: Molecular Structure; Pterins; Pteridines; Coenzymes; Metalloproteins; Oxidation-Reduction
PubMed: 36499560
DOI: 10.3390/ijms232315222 -
Essays in Biochemistry 2011Trypanosomatid parasitic protozoans of the genus Leishmania are autotrophic for both folate and unconjugated pteridines. Leishmania salvage these metabolites from their... (Review)
Review
Trypanosomatid parasitic protozoans of the genus Leishmania are autotrophic for both folate and unconjugated pteridines. Leishmania salvage these metabolites from their mammalian hosts and insect vectors through multiple transporters. Within the parasite, folates are reduced by a bifunctional DHFR (dihydrofolate reductase)-TS (thymidylate synthase) and by a novel PTR1 (pteridine reductase 1), which reduces both folates and unconjugated pteridines. PTR1 can act as a metabolic bypass of DHFR inhibition, reducing the effectiveness of existing antifolate drugs. Leishmania possess a reduced set of folate-dependent metabolic reactions and can salvage many of the key products of folate metabolism from their hosts. For example, they lack purine synthesis, which normally requires 10-formyltetrahydrofolate, and instead rely on a network of purine salvage enzymes. Leishmania elaborate at least three pathways for the synthesis of the key metabolite 5,10-methylene-tetrahydrofolate, required for the synthesis of thymidylate, and for 10-formyltetrahydrofolate, whose presumptive function is for methionyl-tRNAMet formylation required for mitochondrial protein synthesis. Genetic studies have shown that the synthesis of methionine using 5-methyltetrahydrofolate is dispensable, as is the activity of the glycine cleavage complex, probably due to redundancy with serine hydroxymethyltransferase. Although not always essential, the loss of several folate metabolic enzymes results in attenuation or loss of virulence in animal models, and a null DHFR-TS mutant has been used to induce protective immunity. The folate metabolic pathway provides numerous opportunities for targeted chemotherapy, with strong potential for 'repurposing' of compounds developed originally for treatment of human cancers or other infectious agents.
Topics: Amino Acid Oxidoreductases; Animals; Carrier Proteins; Folic Acid; Host-Parasite Interactions; Iron-Sulfur Proteins; Leishmania; Metabolic Networks and Pathways; Methionine; Multienzyme Complexes; Pteridines; Purines; Tetrahydrofolate Dehydrogenase; Tetrahydrofolates; Thymidylate Synthase; Transferases
PubMed: 22023442
DOI: 10.1042/bse0510063 -
Biological Chemistry Aug 2017The biosynthesis of the molybdenum cofactor (Moco) is a highly conserved pathway in bacteria, archaea and eukaryotes. The molybdenum atom in Moco-containing enzymes is... (Review)
Review
The biosynthesis of the molybdenum cofactor (Moco) is a highly conserved pathway in bacteria, archaea and eukaryotes. The molybdenum atom in Moco-containing enzymes is coordinated to the dithiolene group of a tricyclic pyranopterin monophosphate cofactor. The biosynthesis of Moco can be divided into three conserved steps, with a fourth present only in bacteria and archaea: (1) formation of cyclic pyranopterin monophosphate, (2) formation of molybdopterin (MPT), (3) insertion of molybdenum into MPT to form Mo-MPT, and (4) additional modification of Mo-MPT in bacteria with the attachment of a GMP or CMP nucleotide, forming the dinucleotide variants of Moco. While the proteins involved in the catalytic reaction of each step of Moco biosynthesis are highly conserved among the Phyla, a surprising link to other cellular pathways has been identified by recent discoveries. In particular, the pathways for FeS cluster assembly and thio-modifications of tRNA are connected to Moco biosynthesis by sharing the same protein components. Further, proteins involved in Moco biosynthesis are not only shared with other pathways, but additionally have moonlighting roles. This review gives an overview of Moco biosynthesis in bacteria and humans and highlights the shared function and moonlighting roles of the participating proteins.
Topics: Animals; Archaeal Proteins; Bacterial Proteins; Coenzymes; Humans; Metalloproteins; Molybdenum Cofactors; Organophosphorus Compounds; Pteridines; Pterins
PubMed: 28284029
DOI: 10.1515/hsz-2017-0110 -
Molecules (Basel, Switzerland) Nov 2023The parasites () and () cause the tropical diseases sleeping sickness, nagana, and cutaneous leishmaniasis. Every year, millions of humans, as well as animals, living...
The parasites () and () cause the tropical diseases sleeping sickness, nagana, and cutaneous leishmaniasis. Every year, millions of humans, as well as animals, living in tropical to subtropical climates fall victim to these illnesses' health threats. The parasites' frequent drug resistance and widely spread natural reservoirs heavily impede disease prevention and treatment. Due to pteridine auxotrophy, trypanosomatid parasites have developed a peculiar enzyme system consisting of dihydrofolate reductase-thymidylate synthase (DHFR-TS) and pteridine reductase 1 (PTR1) to support cell survival. Extending our previous studies, we conducted a comparative study of the . (DHFR, PTR1) and . (DHFR, PTR1) enzymes to identify lead structures with a dual inhibitory effect. A pharmacophore-based in silico screening of three natural product databases (approximately 4880 compounds) was performed to preselect possible inhibitors. Building on the in silico results, the inhibitory potential of promising compounds was verified in vitro against the recombinant DHFR and PTR1 of both parasites using spectrophotometric enzyme assays. Twelve compounds were identified as dual inhibitors against the enzymes (0.2 μM < IC < 85.1 μM) and ten against the respective enzymes (0.6 μM < IC < 84.5 μM). These highly promising results may represent the starting point for the future development of new leads and drugs utilizing the trypanosomatid pteridine metabolism as a target.
Topics: Humans; Animals; Tetrahydrofolate Dehydrogenase; Leishmania major; Trypanosoma brucei brucei; Pteridines; Trypanosomiasis, African
PubMed: 38005256
DOI: 10.3390/molecules28227526