A molecular switch and electronic circuit modulate catalase activity in catalase‐peroxidases

Abstract

The catalase reaction of catalase‐peroxidases involves catalase‐specific features built into a peroxidase core. An arginine, 20 Å from the active‐site heme, acts as a molecular switch moving between two conformations, one that activates heme oxidation and one that activates oxoferryl heme reduction by H2O2, facilitating the catalatic pathway in a peroxidase. The influence of the arginine is imparted to the heme through its association with or dissociation from a tyrosinate that modulates reactivity through a Met‐Tyr‐Trp crosslinked adduct and a π electron interaction of the heme with the adduct Trp.

Hydrogen peroxide oxidation by catalase‐peroxidase follows a non‐scrambling mechanism

“…Interestingly, this adduct can be associated with a KatG-typical arginine (R439) [2]. Its association with the tyrosinate ion on the adduct is also required for optimum catalatic rates [19,23]. Another important residue at the distal heme cavity is D152, which is part of the substrate channel and has its side chain carboxyl group pointing toward the heme pocket.…”

The role of oxidative stress in α-amanitin-induced hepatotoxicityin an experimental mouse model

“…We found GPx activity in low-and moderate-dose α-amanitin poisoning to be slightly higher than in the controls, but its activity was the same in moderate-and high-dose poisoning groups. In the current literature, investigators have tended not to evaluate hepatocyte GPx activity in α-amanitin poisoning, because they indicated that GPx was responsible for decomposition of H 2 O 2 at low levels of H 2 O 2 and that CAT was responsible at high levels of H 2 O 2 (15,16,29). Conversely, it has been reported that increased ROS load and decreased glutathione levels might play an important role in hepatocyte necrosis induced by toxins, including paracetamol and α-amanitin (26,30 production due to increased SOD activity, and GPx was also involved in the antioxidant mechanisms fighting against an increased ROS load.…”

Functional Implication Guided by Structure-Based Study on Catalase – Peroxidase (KatG) from Haloarcula Marismortui

“…3 (B)) while D125 has been known to be important in thefrom H 2 O 2 , respectively. Hence, the mobile D125 residue will also be suggestive of utilizing as either initiator H 2 O 2 or substrate ODA recognition, making it effective in binding substrate, though disruption of π-complexes with heme and W95 known to act on as molecular switch from the catalase to the peroxidase (Carpena et al, 2005). The amino N of backbone I217 forms an H-bond to the oxygen O 1 of carbonyl group of the side D125.…”

“…The aromatic substrate binding site on heme iron has been identified by determining the structures of [S305A] and its complexes with SHA. These provide a complete description of substrate binding in KatG (Sato et al, 2011b;2011c (Carpena et al, 2005;Jakopitsch et al, 2004;Ghiladi et al, 2004). One of the commonest causes of resistance about INH is also the [R409L] mutation in MtKatG and known for peroxidase reaction (Ghiladi et al, 2004;Saint-joanis et al, 1999).…”

“…The covalent adduct has been shown to be generated by autocatalytic process (Ghiladi et al, 2005a). Crystallographic analysis of KatG from Bulkhorderia pseudomallei (Bp) has indicated that the side-chain of R409 (corresponding to HmKatG numbering) shows conformational change depending on both of pH and the physicochemical state of the active site (Carpena et al, 2005 M244L] in BpKatG considerably decreased the catalase activity, whereas the peroxidase activity was even enhanced (Regelsberger et al, 2000;Jakopitsch et al, 2004;Singh et al, 2004 Y218F] in the M244-Y218-W95 covalent adducts induced complete loss of the catalase activity, whereas the peroxidase activity was highly enhanced in Sy KatG (Jakopitsch et al, 2003a;Jakopitsch,et al, 2003b). M244 in the adduct also has any significant role in the enzyme, whereas the substitution of Met to Ile considerably attenuated the catalase activity but did not lose at all, and enhanced the peroxidase activity Singh et al, 2004).…”