Inverse Association of Plasma Molybdenum with Metabolic Syndrome in a Chinese Adult Population: A Case-Control Study.

Molybdenum has been found to be associated with metabolic disorders. However, the relationship between molybdenum and metabolic syndrome (MetS) is still unclear. A large case-control study was conducted in a Chinese population from the baseline of Ezhou-Shenzhen cohort. A total of 5356 subjects were included with 2678 MetS and 2678 controls matched by sex and age (±2 years). Medians (IQRs) of plasma molybdenum concentrations were 1.24 µg/L for MetS cases and 1.46 µg/L for controls. After adjustment for multiple covariates, the odds ratio (OR) and 95% confidence intervals (CIs) for MetS were 1.00 (reference), 0.71 (0.59-0.84), 0.56 (0.46-0.68), and 0.47 (0.39-0.58) across quartiles of plasma molybdenum, and per SD increment of log-transformed molybdenum was associated with a 23% lower risk of MetS. In the spline analysis, the risk of MetS and its components decreased steeply with increasing molybdenum and followed by a plateau when the cutoff point was observed around 2.0 µg/L. The dose-dependent relationship of molybdenum with MetS remained consistent when considering other essential elements in the Bayesian kernel machine regression (BKMR) model. In our study, higher plasma molybdenum was significantly associated with a lower risk of MetS, as well as its components, in a dose-response manner.

Protein-Derived Cofactors Revisited: Empowering Amino Acid Residues with New Functions.

A protein-derived cofactor is a catalytic or redox-active site in a protein that is formed by post-translational modification of one or more amino acid residues. These post-translational modifications are irreversible and endow the modified amino acid residues with new functional properties. This Perspective focuses on the following advances in this area that have occurred during recent years. The biosynthesis of the tryptophan tryptophylquinone cofactor is catalyzed by a diheme enzyme, MauG. A bis-FeIV redox state of the hemes performs three two-electron oxidations of specific Trp residues via long-range electron transfer. In contrast, a flavoenzyme catalyzes the biosynthesis of the cysteine tryptophylquinone (CTQ) cofactor present in a newly discovered family of CTQ-dependent oxidases. Another carbonyl cofactor, the pyruvoyl cofactor found in classes of decarboxylases and reductases, is formed during an apparently autocatalytic cleavage of a precursor protein at the N-terminus of the cleavage product. It has been shown that in at least some cases, the cleavage is facilitated by binding to an accessory protein. Tyrosylquinonine cofactors, topaquinone and lysine tyrosylquinone, are found in copper-containing amine oxidases and lysyl oxidases, respectively. The physiological roles of different families of these enzymes in humans have been more clearly defined and shown to have significant implications with respect to human health. There has also been continued characterization of the roles of covalently cross-linked amino acid side chains that influence the reactivity of redox-active metal centers in proteins. These include Cys-Tyr species in galactose oxidase and cysteine dioxygenase and the Met-Tyr-Trp species in the catalase-peroxidase KatG.

[Metabolic correction: a biochemical option against diseases]. / Corrección metabólica: Una opción bioquímica contra las enfermedades.

Human development and its physiology depends on a number of complex biochemical body processes, many of which are interactive and codependent. The speed and the degree in which many physiological reactions are completed depend on enzyme activity, which in turn depends on the bioavailability of co-factors and micronutrients such as vitamins and minerals. To achieve a healthy physiological state, organism need that biochemical reactions occur in a controlled and specific way at a particular speed and level or grade fully completed. To achieve this, is required an optimal metabolic balance. Factors such as, a particular genetic composition, inadequate dietary consumption patterns, traumas, diseases, toxins and environmental stress all of these factors rising demands for nutrients in order to obtain optimal metabolic balance. Metabolic correction is a biochemical and physiological concept that explains how improvements in cellular biochemistry of an organism can help the body achieve metabolic and physiological optimization. We summarize the contribution of several pioneers in understanding the role of micronutrients in health management. The concept of metabolic correction is becoming a significant term due to the presence of genetic variants that affect the speed of reactions of enzymes, causing metabolic alterations that enhance or promote the state/development of multiple diseases. Decline in the nutritional value of the food we eat, the increase in demand for certain nutrients caused by normal development, diseases and medications induce, usually, nutrients consumption. These nutritional deficiencies and insufficiencies are causing massive economic costs due to increased morbidity and mortality in our society. In summary, metabolic correction improves the enzymatic function, which favors the physiological normal functions, thus, contributing to improving health and the welfare of the human being. The purpose of this paper is to describe and introduce the concept of optimal metabolic correction as a functional cost-effective mechanism against disease, in addition, to contribute to diseases prevention and regeneration of the body and health.

Refining the pathway of carbide insertion into the nitrogenase M-cluster.

Carbide insertion plays a pivotal role in the biosynthesis of M-cluster, the cofactor of nitrogenase. Previously, we proposed a carbide insertion pathway involving methyltransfer from SAM to a FeS precursor and hydrogen abstraction from this methyl group that initiates the radical-based precursor maturation. Here we demonstrate that the methyl group is transferred to a precursor-associated sulfur before hydrogen abstraction, thereby refining the initial steps of the carbide insertion pathway.

Structure and function of Fic proteins.

Fic proteins are a family of proteins characterized by the presence of a conserved FIC domain that is involved in the modification of protein substrates by the addition of phosphate-containing compounds, including AMP and other nucleoside monophosphates, phosphocholine and phosphate. Fic proteins are widespread in bacteria, and various pathogenic species secrete Fic proteins as toxins that mediate post-translational modifications of host cell proteins, to interfere with cytoskeletal, trafficking, signalling or translation pathways in the host cell. In this Review, we discuss the current knowledge of the structure, function and regulation of Fic proteins and consider important areas for future research.

Lipophilic modification enhances anti-colitic properties of rosmarinic acid by potentiating its HIF-prolyl hydroxylases inhibitory activity.

Inhibition of hypoxia inducible factor-prolyl hydroxylase-2 (HPH), leading to activation of hypoxia inducible factor (HIF)-1 is a potential therapeutic strategy for the treatment of colitis. Rosmarinic acid (RA), an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid is a naturally occurring polyphenolic compound with two catechols, a or inhibition of HPH. To improve accessibility of highly hydrophilic RA to HPH, an intracellular target, RA was chemically modified to decrease hydrophilicity. Of the less-hydrophilic derivatives, rosmarinic acid methyl ester (RAME) most potently inhibited HPH. Accordingly, RAME prevented hydroxylation of HIF-1α and consequently stabilized HIF-1α protein in cells. RAME inhibition of HPH and induction of HIF-1α were diminished by elevated doses of the required factors of HPH, 2-ketoglutarate and ascorbate. RAME induction of HIF-1α led to activation of an ulcer healing pathway, HIF-1-vascular endothelial growth factor (VEGF), in human colon carcinoma cells. RAME administered rectally ameliorated TNBS-induced rat colitis and substantially decreased the levels of pro-inflammatory mediators in the inflamed colonic tissue. In parallel with the cellular effects of RAME, RAME up-regulated HIF-1α and VEGF in the inflamed colonic tissue. Thus, lipophilic modification of RA improves its ability to inhibit HPH, leading to activation of the HIF-1-VEGF pathway. RAME, a lipophilic RA derivative, may exert anti-colitic effects via activation of the ulcer healing pathway.

Unusual cytochrome p450 enzymes and reactions.

Cytochrome P450 enzymes primarily catalyze mixed-function oxidation reactions, plus some reductions and rearrangements of oxygenated species, e.g. prostaglandins. Most of these reactions can be rationalized in a paradigm involving Compound I, a high-valent iron-oxygen complex (FeO(3+)), to explain seemingly unusual reactions, including ring couplings, ring expansion and contraction, and fusion of substrates. Most P450s interact with flavoenzymes or iron-sulfur proteins to receive electrons from NAD(P)H. In some cases, P450s are fused to protein partners. Other P450s catalyze non-redox isomerization reactions. A number of permutations on the P450 theme reveal the diversity of cytochrome P450 form and function.

A variant conferring cofactor-dependent assembly of Escherichia coli dimethylsulfoxide reductase.

We have investigated the final steps of complex iron-sulfur molybdoenzyme (CISM) maturation using Escherichia coli DMSO reductase (DmsABC) as a model system. The catalytic subunit of this enzyme, DmsA, contains an iron-sulfur cluster (FS0) and a molybdo-bis(pyranopterin guanine dinucleotide) cofactor (Mo-bisPGD). We have identified a variant of DmsA (Cys59Ser) that renders enzyme maturation sensitive to molybdenum cofactor availability. DmsA-Cys59 is a ligand to the FS0 [4Fe-4S] cluster. In the presence of trace amounts of molybdate, the Cys59Ser variant assembles normally to the cytoplasmic membrane and supports respiratory growth on DMSO, although the ground state of FS0 as determined by EPR is converted from high-spin (S=3/2) to low-spin (S=1/2). In the presence of the molybdenum antagonist tungstate, wild-type DmsABC lacks Mo-bisPGD, but is translocated via the Tat translocon and assembles on the periplasmic side of the membrane as an apoenzyme. The Cys59Ser variant cannot overcome the dual insults of amino acid substitution plus lack of Mo-bisPGD, leading to degradation of the DmsABC subunits. This indicates that the cofactor can serve as a chemical chaperone to mitigate the destabilizing effects of alteration of the FS0 cluster. These results provide insights into the role of the Mo-bisPGD-protein interaction in stabilizing the tertiary structure of DmsA during enzyme maturation.

Beyond the resistance: how novel neurobiological understandings of depression may lead to advanced treatment strategies.

For patients with depression, antidepressant response rates are generally low and residual symptoms can increase the risk of relapse. Poor response may be linked to increased inflammatory cytokines and obesity. Specifically targeting inflammation with adjunct l-methylfolate treatment may help patients with depression finally achieve remission. In this Webcast, experts examine the multi-directional relationship between obesity, inflammation, and depression, consider preliminary data on genetic alleles, and review evidence using l-methylfolate as a targeted therapy.

Tissue factor and glycoprotein C on herpes simplex virus type 1 are protease-activated receptor 2 cofactors that enhance infection.

The coagulation system provides physiologic host defense, but it can also be exploited by pathogens for infection. On the HSV1 surface, host-cell-derived tissue factor (TF) and virus-encoded glycoprotein C (gC) can stimulate protease activated receptor 1 (PAR1)-enhanced infection by triggering thrombin production. Using novel engineered HSV1 variants deficient in either TF and/or gC, in the present study, we show that activated coagulation factors X (FXa) or VII (FVIIa) directly affect HSV1 infection of human umbilical vein endothelial cells in a manner that is dependent on viral TF and gC. The combination of FXa and FVIIa maximally enhanced infection for TF(+)/gC(+) HSV1 and receptor desensitization and Ab inhibition demonstrated that both proteases act on PAR2. Inhibitory TF Abs showed that the required TF source was viral. Individually, TF or gC partly enhanced the effect of FXa, but not FVIIa, revealing gC as a novel PAR2 cofactor for FVIIa. In sharp contrast, thrombin enhanced infection via PAR1 independently of viral TF and gC. Thrombin combined with FXa/FVIIa enhanced infection, suggesting that PAR1 and PAR2 are independently involved in virus propagation. These results show that HSV1 surface cofactors promote cellular PAR2-mediated infection, indicating a novel mode by which pathogens exploit the initiation phase of the host hemostatic system.

Vitamin B6: beyond coenzyme functions.

Endogenous reactive intermediates such as photoexcited states of tissue chromophores, reactive oxygen species (ROS), reactive carbonyl species (RCS), and transition metal ions are mediators of tissue damage involved in initiation and progression of human pathologies including tumorigenesis, atherosclerosis, diabetes, and neurodegenerative disease. A large body of evidence now suggests that B6 vitamers antagonize the harmful activity of endogenous reactive intermediates fulfilling a very different role than that established as a cofactor for numerous enzymes. In this chapter, the structural basis of vitamin B6 activity as a potent antioxidant, metal chelator, carbonyl scavenger, and photosensitizer is presented and the physiological relevance is discussed.

The biochemical roots of the RNA world: from zymonucleic acid to ribozymes.

The history of the ideas that led to the RNA World hypothesis is reviewed. As the understanding of the properties of RNA molecules progressed, the evolutionary interpretation of their genetic properties and widespread distribution in intracellular environments, as well as the catalytic properties of nucleotide coenzymes and the participation of RNA monomers in metabolic pathways, led to several independent proposals of protein-free primordial life forms. Current ideas on the RNA World are part of a long and storied scientific perspective in which these different hypotheses were developed. However, the lack of continuity between them may be explained in part by the absence of an evolutionary framework that characterized the early development of molecular biology, as well as by the demise of certain areas of research like coenzyme chemistry.

Lipids in photosystem II: multifunctional cofactors.

To maintain its functionality, photosystem II (PSII) employs several types of auxiliary molecules (cofactors). As shown for PSII from Thermosynechococcus elongatus, lipids previously thought to play mostly the role of a hydrophobic matrix for embedding the membrane proteins, must be considered as a new, multifunctional type of cofactors, playing a vital role in the fine tuning of PSII and in its overall operation. The 2.9 Å resolution crystal structure of cyanobacterial homodimeric PSII showed the position of 25 lipid molecules per monomer, and allowed detailed analysis of individual binding sites as well as functional aspects related to lipids. The positions of the bound lipids suggest that they are essential for the assembly and disassembly of PSII, provide the proper environment for plastoquinone exchange, might tune electron transfer through contacts with chlorophylls and carotenoids, and might serve as an oxygen-outlet system from the lumen.

Role of the azadithiolate cofactor in models for [FeFe]-hydrogenase: novel structures and catalytic implications.

This paper summarizes studies on the redox behavior of synthetic models for the [FeFe]-hydrogenases, consisting of diiron dithiolato carbonyl complexes bearing the amine cofactor and its N-benzyl derivative. Of specific interest are the causes of the low reactivity of oxidized models toward H(2), which contrasts with the high activity of these enzymes for H(2) oxidation. The redox and acid-base properties of the model complexes [Fe(2)[(SCH(2))(2)NR](CO)(3)(dppv)(PMe(3))](+) ([2](+) for R = H and [2'](+) for R = CH(2)C(6)H(5), dppv = cis-1,2-bis(diphenylphosphino)ethylene)) indicate that addition of H(2) followed by deprotonation are (i) endothermic for the mixed valence (Fe(II)Fe(I)) state and (ii) exothermic for the diferrous (Fe(II)Fe(II)) state. The diferrous state is shown to be unstable with respect to coordination of the amine to Fe, a derivative of which was characterized crystallographically. The redox and acid-base properties for the mixed valence models differ strongly for those containing the amine cofactor versus those derived from propanedithiolate. Protonation of [2'](+) induces disproportionation to a 1:1 mixture of the ammonium [H2'](+) (Fe(I)Fe(I)) and the dication [2'](2+) (Fe(II)Fe(II)). This effect is consistent with substantial enhancement of the basicity of the amine in the Fe(I)Fe(I) state vs the Fe(II)Fe(I) state. The Fe(I)Fe(I) ammonium compounds are rapid and efficient H-atom donors toward the nitroxyl compound TEMPO. The atom transfer is proposed to proceed via the hydride. Collectively, the results suggest that proton-coupled electron-transfer pathways should be considered for H(2) activation by the [FeFe]-hydrogenases.

Esmond E. Snell--the pathfinder of B vitamins and cofactors.

Esmond E. Snell (1914-2003) was a giant of B-vitamin and enzyme research. His early research in bacterial nutrition had lead to the discovery of vitamins such as lipoic acid and folic acid, and an anti-vitamin avidin. He developed microbiological assay methods for riboflavin and other vitamins and amino acids, which are still used today. He also investigated the metabolism of vitamins, discovered pyridoxal and pyridoxamine as the active forms of vitamin B(6) and revealed the mechanism of transamination and other reactions catalysed by vitamin B(6) enzymes. His research in later years on pyruvoyl-dependent histidine decarboxylase unveiled the biogenesis mechanism of this first built-in cofactor. Throughout his career, he was a great mentor of many people, all of whom are inspired by his philosophy of science.

Context dependence of proneural bHLH proteins.

A key point in neural development is the commitment of progenitor cells to a specific neural fate. In all animals studied, proneural proteins - transcription factors of the basic helix-loop-helix (bHLH) family - are central to this process. The function of these factors is strongly influenced by the spatial and temporal context in which they are expressed. It is important to understand the molecular mechanisms by which developmental context interacts with and modifies the intrinsic functions and properties of the proneural proteins. Recent insights have been obtained in Drosophila and vertebrates from analysis of how bHLH proteins interact with other transcription factors to regulate target genes.

Mecobalamin.

BACKGROUND: Mecobalamin, one of the coenzyme forms of vitamin B(12), acts as an important cofactor in the activities of B(12)-dependent methyltransferases. Since the discovery of mecobalamin, it has been applied mainly in the treatment of hyperhomocysteinaemia and peripheral neuropathy. However, there is still lack of a systemic review on the clinical administration of mecobalamin and its potential mechanism. OBJECTIVE: To review the mechanism, clinical efficacy and safety of mecobalamin in the treatment of hyperhomocysteinaemia and peripheral neuropathy. METHODS: First, the potential mechanism, pharmacokinetics and metabolism of mecobalamin were clarified. In addition, the clinical administration including efficacy, safety and tolerability of mecobalamin as monotherapy or combined therapy in the treatment of hyperhomocysteinaemia and peripheral neuropathy were also detailed. RESULTS/CONCLUSIONS: Although both monotherapy and combined therapy can lower plasma/serum homocysteine levels and improve the neuropathic symptoms, combined therapy with other B vitamins seems to be more effective. However, more precise, double-blind and randomised control studies are necessary to confirm the efficacy of mecobalamin on hyperhomocysteinaemia, peripheral neuropathy interaction, and cardiovascular, neurological and osteoporotic mortality or morbidity.