Gudmundsdttir et al.2006; Imrie et al.2009; Purdey2000; Stevens et al.2009). == Iron deposition and disease: cause or effect? The case of atherosclerosis == I have implied that the role of unliganded iron iscausativeof a variety of sequelae, but sometimes this is hard to infer as the networks in which iron is involved are multiple and complex (hence the need for a systems approachsee later), and often simple one-time snapshots of covariates do not permit the inference of causality. dysregulation. This highlights specifically the role of iron metabolism, and the detailed speciation of iron, in chemical and other toxicology, and has significant KRAS G12C inhibitor 15 implications for the use of iron chelating substances (probably inpartnershipwith appropriate anti-oxidants) as nutritional or therapeutic agents in inhibiting both KRAS G12C inhibitor 15 the progression of these mainly degenerative diseases and the sequelae of both chronic and acute toxin exposure. The complexity of biochemical networks, especially those involving autocatalytic behaviour and positive feedbacks, means that multiple interventions (e.g. of iron chelators plus antioxidants) are likely to prove most effective. A variety of systems biology approaches, that I summarise, can predict both the mechanisms involved in these cell death pathways and the optimal sites of action for nutritional or pharmacological interventions. Keywords:Antioxidants, Apoptosis, Atherosclerosis, Cell death, Chelation, Chemical toxicology, Iron, Neurodegeneration, Phlebotomy, Polyphenols, Sepsis, SIRS, Stroke, Systems biology, Toxicity == Introduction == As a transition metal that can exist in several valencies, and that can bind up to six ligands, iron is an important component of KRAS G12C inhibitor 15 industrial catalysts in the chemical industry (Hagen2006), especially for redox reactions. Its catalysis of specific reactions requires rather exact architectures at the catalytic centre, and indeed much of the art and science of catalyst production involves determining and synthesising them. Nearly half of all enzymes are metalloproteins (Waldron et al.2009), and iron is also of considerable importance in biology as a component of all kinds of metalloproteins (Andreini et al.2008,2009) from haemoglobin to cytochromes, as well as in the directed evolution ofnovelenzyme activities (Pordea and Ward2008; Que and Tolman2008; Turner2009). When serving in enzymes, the iron is normally safely liganded, and any reactions catalysed are usually fairly specific. However, as is widely KRAS G12C inhibitor 15 recognised, iron can also have a dark side (Kell2009a), in that when it is not properly liganded (Graf et al.1984), and in the ferrous form, it can react with hydrogen peroxide (produced by mitochondria (e.g. Brennan and Kantorow2009; Fato et al.2008; Orrenius et al.2007) or (per)oxidases (Bedard and Krause2007; Cave et al.2006) via the Fenton reaction (Goldstein et al.1993; Rabbit Polyclonal to ABHD12 Kruszewski2003; Toyokuni2002; Wardman and Candeias1996; Winterbourn1995), leading to the very reactive and damaging hydroxyl radical (OH) Superoxide (also produced by mitochondria) can react with ferric iron in the Haber-Weiss reaction (Kehrer2000) to produce Fe(II) again, thereby effecting redox cycling of the iron (Fig.1): == Fig. 1. == The Haber-Weiss and Fenton reactions combine using poorly liganded iron in acatalytic cycleto produce the very damaging hydroxyl radical. Poorly liganded iron can also be liberated via the destruction of haem and other iron-containing substances. Peroxynitrite anion (ONOO) is produced by the reaction of superoxide and nitric oxide (NO) which when protonated (pH ca 6.56.8) decomposes to OHand NO2 Ascorbate (vitamin C) can also replacefor reducing the Fe(III) to Fe(II) (Hershko and Weatherall1988), as can other reducing agents, and indeed too low a redox poise leads to DNA damage (e.g. Li and Marbn2010; Seifried et al.2007). The hydroxyl radical is exceptionally reactive and damaging to cellular components, and, for instance, can liberate further Fe(II) from iron-sulphur centres and other iron-containing compounds such as ferritin (Arosio et al.2009), thereby driving reaction (1) in an autocatalytic, runaway kind of reaction. This kind of phenomenon has the potential to overwhelm any kinds of attempts at repair, and inflammation and oxidative stress are the hallmarks of each of the conditions I summarise. Related reactions include peroxynitrite production (from the reaction of NO and superoxide) (Babior2000; Beckman et al.1990; Beckman and Koppenol1996; Goldstein and Mernyi2008; Koppenol et al.1992; Murphy et al.1998; Pacher et al.2007; Pavlovic and Santaniello2007; Pryor and Squadrito1995; Radi et al.2001,2002; Rubbo and ODonnell2005; Rubbo et al.2009; Smith et al.1997b; Squadrito and Pryor1998; Szabo1996; Szab et al.2007; Torreilles et al.1999; White et al.1994; Zimmet and.
Gudmundsdttir et al
