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Vitamin C in Pneumonia and Sepsis
Published in Qi Chen, Margreet C.M. Vissers, 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].
Nutritional Ergogenic Aids: Introduction, Definitions and Regulatory Issues
Published in Ira Wolinsky, Judy A. Driskell, Nutritional Ergogenic Aids, 2004
Ira Wolinsky, Judy A. Driskell
In humans, carnitine is synthesized from the essential amino acids lysine and methionine.9,23-25 Methionine contributes its methyl groups26-27 and the carbon and nitrogen moieties come from lysine.28-29 In addition, ascorbic acid, iron, niacin and vitamin B6 are all requirements for the biosynthesis of carnitine.30 (Figure 5.3). The liver, kidney, heart and skeletal muscle can convert the trimethyl lysine, which originates from digestion of proteins, to g-butyrobetaine, but studies have shown that in humans only the liver and kidney can convert g-butyrobetaine to carnitine.8,9,31 This has several implications because the heart and skeletal muscles need carnitine but do not produce it, thus carnitine’s transport efficiency is critical, especially during activities such as exercise. Carnitine biosynthesis occurs at a rate of two mol/kg of body weight-1/day-1, does not experience significant daily fluctuations, and seems to be related to the availability of N-trimethlyllysine.23 As mentioned previously, the diet can provide a significant amount of carnitine, approximately 50% (100-300 mg/daily) in the form of either free carnitine or short- and long-chain fatty acids.32,33 This is true for individuals who consume large amounts of beef, pork and lamb. In addition, this intake is sufficient to maintain normal carnitine homeostasis. Vegetarians who consume less than 0.5 mmol/kg of body weight-1/day-1 must rely on endogenous production of carnitine to maintain homeostasis.34
Emerging drug targets for triple-negative breast cancer: a guided tour of the preclinical landscape
Published in Expert Opinion on Therapeutic Targets, 2022
Xuemei Xie, Jangsoon Lee, Toshiaki Iwase, Megumi Kai, Naoto T Ueno
Cancer cells utilize aerobic glycolysis (the Warburg effect) and anaerobic respiration (oxidative phosphorylation) to overcome metabolic stress. Gamma-butyrobetaine hydroxylase 1 (BBOX1), a member of the 2-oxoglutarate-dependent enzyme family, catalyzes L-carnitine biosynthesis from gamma-butyrobetaine. The carnitine pathway is a crucial mediator of cancer metabolic plasticity that provides an energetic and biosynthetic demand for cancer cells [123]. BBOX1 expression is correlated with poor prognosis in TNBC [124]. Furthermore, BBOX1 was required for both mitochondrial activity and mTORC1-dependent glycolysis, and BBOX1 knockdown significantly suppressed in vivo TNBC tumorigenesis, suggesting BBOX1 as a new druggable target for TNBC [124]. Several small molecules, e.g. AR692B and C-2124, were identified as BBOX1 inhibitors. However, in vitro half-maximal inhibitory concentrations of these inhibitors were high (>100 µM) [124], indicating that they would not have strong anti-tumor efficacy in animal models. Therefore, more specific and potent BBOX1 inhibitors are needed.