Vitamin C in Pneumonia and Sepsis
Qi Chen, Margreet C.M. Vissers in Vitamin C, 2020
One of the primary roles of vitamin C in the body is to act as a cofactor for a family of metalloenzymes with various biosynthetic and regulatory roles [111–113]. These enzymes introduce hydroxyl groups into biomolecules and comprise two main categories: iron- and 2-oxoglutarate–dependent dioxygenases and copper-containing monooxygenases. Of the former category, vitamin C has long been known to act as a cofactor for the lysyl and prolyl hydroxylases required for stabilization of the tertiary structure of collagen, an essential component of the vasculature [114]. Vitamin C may also be able to stimulate the expression of collagen mRNA, perhaps through its gene regulatory mechanisms described later [77]. Similarly, vitamin C is a cofactor for the two hydroxylases involved in carnitine biosynthesis, a molecule required for transport of fatty acids into mitochondria for generation of metabolic energy [115]. Mitochondrial dysfunction and depleted ATP levels are observed in sepsis; thus, vitamin C may be able to contribute to metabolic resuscitation via both antioxidant and cofactor mechanisms [116,117].
Steroid Carboxylic Acids
Ronald Hobkirk in Steroid Biochemistry, 1979
In a careful series of studies, Sih and his colleagues have explored the mechanism by which rings A and B of androstenedione are degraded (Figure 5). The first step105,107,110 is hydroxylation at C-9 and dehydrogenation at C1,2 in either order to yield 3-hydroxy-9,10-secoandrosta-1,3,5(10)-triene-9,17-dione. This is further hydroxylated to the corresponding 3,4-dihydroxy compound.111 This is cleaved by a dioxygenase to yield 4(5),9(10)-diseco-3-hydroxyandrosta(l,10),2-diene 5,9,17-trion-4-oic acid.112 The cleavage is similar to the cleavage of a variety of catechols.113,114 This oxidation, as Sih has noted, represents the first positive demonstration of a dioxygenase enzyme in the microbial metabolism of steroids. Ring A is split off as 2-oxo-4-hydroxy caproic acid which is, in turn, enzymatically hydrolyzed to propionaldehyde and pyruvic acid. Rings C and D remain as 3aα H-4α(3’ propionic acid)7aβ-methyl hexahydro-1,5-indanenedione (Figure 5). Incubation of estrone yielded a related acid with 4-buten-3-oic acid attached at C-5 (Structure V) because of the failure to further metabolize the aromatic ring A. When either the 1,2-dehydrogenation or 9α-hydroxylation reactions are blocked, further degradation is inhibited.109 This enzymatic sequence is relatively nonspecific in terms of the functional group at C-17.
Subfamily Bombacoideae
Mahendra Rai, Shandesh Bhattarai, Chistiane M. Feitosa in Wild Plants, 2020
The inflammatory processes may also activate some biomarkers, such as cyclooxygenases, which are enzymes that allow the body to produce prostaglandins from arachidonic acid. This type of enzymes can act as dioxygenase or peroxidase, as they are peripheral membrane proteins having two isoforms (Salinas et al. 2007). COX1, present in most tissues, such as stomach, synthesize prostaglandins and perform maintenance of the gastric mucosa, which regulates the proliferation of normal cells and intervenes indirectly in physiological processes, such as protection and neutrophil migration to the epithelium. COX2, the other isoform, is formed from an increase of prostaglandins in tissues where an inflammatory response occurs. It is expressed after induction of inflammation caused by erosion of the mucosa (Díaz-Rivas et al. 2015). Inhibition of both COX-1 and COX-2 was found to be the basic mechanism of different anti-inflammatory plant extracts. However, selective COX-2 inhibitor mixes both the anti-inflammatory activity and minimum side effects usually related to COX-1 inhibition. The isoflavone compounds isolated from Ceiba pentandra stem bark were evaluated for their inhibition of cyclooxygenase-1-catalyzed prostaglandin biosynthesis together with the known flavan-3-ol, (+)-catechin (39). Vavain (45), vavain 3‘-O-β-D-glucoside (46), and (+)-catechin (39) demonstrated inhibitory effects with IC50 values of 97, 381, and 80 μM, respectively, compared to indomethacin activity (IC50 of 1.1 μM) (Noreen et al. 1998).
Phenylalanine 4-monooxygenase: the “sulfoxidation polymorphism”
Published in Xenobiotica, 2020
Stephen C. Mitchell, Glyn B. Steventon
Another fundamental problem is that the enzyme is generally regarded as a dioxygenase, attaching two oxygen atoms derived from molecular oxygen to form a sulfinic acid and not an unstable sulfenic acid. If it were to be involved in the metabolism of S-carboxymethyl-l-cysteine it would more likely produce a sulfone rather than a sulfoxide and trace amounts of the sulfone metabolite have only been reported once in human urine and may have been an artefact (Brockmoller et al., 1988). In general, compounds with a free sulfhydryl group are unable to form stable sulfenic acids, these compounds being transient intermediates that undergo disproportionation or self-condensation. To attain stability they require a polar or bulky grouping adjacent to the sulfenic acid moiety (Barrett, 1990; Hogg, 1990). With regards to cysteine, the sulfhydryl group needs to be substituted replacing the hydrogen atom with a more substantial moiety. S-carboxymethyl-l-cysteine is such a molecule with a carboxymethyl (–CH2COOH) entity being attached forming a thioether which may then produce a stable S-oxide. However, it is this addition to the cysteine molecule that presumably interferes with binding to the cysteine dioxygenase enzyme and moves the sulfur atom away from the catalytic site.
Single-center, observational study of AML/MDS-EB with IDH1/2 mutations: genetic profile, immunophenotypes, mutational kinetics and outcomes
Published in Hematology, 2023
Vasiliki Papadopoulou, Jacqueline Schoumans, Valentin Basset, Françoise Solly, Jérôme Pasquier, Sabine Blum, Olivier Spertini
IDH (isocitrate dehydrogenase) enzymes convert, via a two-step process, isocitrate to α-ketoglutarate (α-KG), within and outside of, the Krebs cycle [1]. α-KG produced from isocitrate can serve as a substrate (OH-donor) for dioxygenase-type enzymes. Dioxygenase-type enzymes include, among others, histone demethylases and DNA-5-methylcytosine hydroxylases like TET2. Therefore, as hydroxylation of the 5-methylcytosines of DNA is the first step to DNA demethylation [2,3], the activity of IDH1/2 enzymes, ultimately serves, among other purposes, to promote DNA and histone demethylation by providing to dioxygenases the substrate α-KG, and thus to activate certain gene expression signatures [4]. Mutations of IDH1/2 are frequent in gliomas and cartilaginous tumors [5,6] and occur recurrently in AML and MDS [7]. IDH1 mutations typically alter the R132 residue of the active site, while mutations in IDH2 similarly alter an active-site arginine at position 140 or 172 [4,7]. Disturbance of the active site leads to production of D-2-hydroxyglutarate (D-2-HG), instead of α-KG, a product with ability to inhibit dioxygenase-type enzymes, instead of serving as their substrate [8–10]. Therefore, both histone and DNA demethylation are ultimately inhibited by the non-physiological product D-2-HG and a hypermethylated genome/epigenome is expected, and has been shown, in IDH1/2-mutated malignancies [11–13].
Challenges in the management of HIV infection: update on the role of probiotic supplementation as a possible complementary therapeutic strategy for cART treated people living with HIV/AIDS
Published in Expert Opinion on Biological Therapy, 2019
Giancarlo Ceccarelli, Maura Statzu, Letizia Santinelli, Claudia Pinacchio, Camilla Bitossi, Eugenio Nelson Cavallari, Vincenzo Vullo, Carolina Scagnolari, GabrieIla d’Ettorre
AHR activation by dietary ligands maintains intestinal barrier integrity, restores barrier homeostasis and influences the regeneration of intestinal epithelial cells upon injury through infection [50–55]. In the context of intestinal homeostasis, recent studies revealed that induction of indoleamine 2,3-dioxygenase (IDO), and the consequent modification of tryptophan metabolism pathway, depends on AHR expression. In particular, AHR contributes to immune homeostasis with an anti-inflammatory activity through the mediation of IDOdependent development of regulatory T cells and Th17 cells [56,57]. Moreover, the immune tolerance between the host and commensal microbiota is maintained and sustained by a positive feedback loop between AHR, IDO and kynurenine, one of the components of the pathway of tryptophan metabolism [58].
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