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Can gas replace protein function? CO abrogates the oxidative toxicity of myoglobin.

Sher EA, Sholto AY, Shaklai M, Shaklai N - PLoS ONE (2014)

Bottom Line: The main cause of LDL oxidation by Hb was found to be hemin which readily transfers from Hb to LDL.These reactions were fully arrested by CO.The data are interpreted to suit several circumstances, some physiological, such as high muscle activity, and some pathological, such as rhabdomyolysis, ischemia/reperfusion and skeletal muscle disuse atrophy.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

ABSTRACT
Outside their cellular environments, hemoglobin (Hb) and myoglobin (Mb) are known to wreak oxidative damage. Using haptoglobin (Hp) and hemopexin (Hx) the body defends itself against cell-free Hb, yet mechanisms of protection against oxidative harm from Mb are unclear. Mb may be implicated in oxidative damage both within the myocyte and in circulation following rhabdomyolysis. Data from the literature correlate rhabdomyolysis with the induction of Heme Oxygenase-1 (HO-1), suggesting that either the enzyme or its reaction products are involved in oxidative protection. We hypothesized that carbon monoxide (CO), a product, might attenuate Mb damage, especially since CO is a specific ligand for heme iron. Low density lipoprotein (LDL) was chosen as a substrate in circulation and myosin (My) as a myocyte component. Using oxidation targets, LDL and My, the study compared the antioxidant potential of CO in Mb-mediated oxidation with the antioxidant potential of Hp in Hb-mediated oxidation. The main cause of LDL oxidation by Hb was found to be hemin which readily transfers from Hb to LDL. Hp prevented heme transfer by sequestering hemin within the Hp-Hb complex. Hemin barely transferred from Mb to LDL, and oxidation appeared to stem from heme iron redox in the intact Mb. My underwent oxidative crosslinking by Mb both in air and under N2. These reactions were fully arrested by CO. The data are interpreted to suit several circumstances, some physiological, such as high muscle activity, and some pathological, such as rhabdomyolysis, ischemia/reperfusion and skeletal muscle disuse atrophy. It appear that CO from HO-1 attenuates damage by temporarily binding to deoxy-Mb, until free oxygen exchanges with CO to restore the equilibrium.

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Differences in Hb and Mb induced oxidation yield distinct protection mechanisms.In presence of peroxide, ferrous RH are oxidized to their ferric (FeIII) and/or ferryl (FeIV) forms. Upper: Hp binds Hb (ferrous and/or ferric) thereby preventing its release. Lower: Mb heme is retained attached to globin following oxidation in a peroxidase-like form. However, binding of CO to ferrous Mb prevents its oxidation to a ‘peroxidase-like form”.
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pone-0104075-g009: Differences in Hb and Mb induced oxidation yield distinct protection mechanisms.In presence of peroxide, ferrous RH are oxidized to their ferric (FeIII) and/or ferryl (FeIV) forms. Upper: Hp binds Hb (ferrous and/or ferric) thereby preventing its release. Lower: Mb heme is retained attached to globin following oxidation in a peroxidase-like form. However, binding of CO to ferrous Mb prevents its oxidation to a ‘peroxidase-like form”.

Mentions: The prominent difference between the two mechanisms by which Hb and Mb act, relates to the fact that heme transfer from Mb is negligible in comparison to Hb (Fig. 5). Differences in mechanisms of the two proteins are especially prominent when observing the kinetics of LDL oxidation and its arrest by CO (Fig. 7, main). LDL is oxidized by ferric-Mb at a constant rate, appropriate for enzymatic function. This differs completely from the multistage rate of Hb-induced LDL oxidation (Fig. 7 insert). Despite a common physiological function (oxygen binding to a divalent heme iron), Hb and Mb differ in the mechanism by which they evoke oxidation. Hb oxidative activity results fundamentally from a weakening of the trivalent heme-globin bond [44]. As discussed earlier, ferric-Hb redox activity is manifested by the presence of components that bind hemin strongly, such as LDL [6], [33]. Thus, only a high–affinity globin–binding protein, such as Hp, can efficiently trap hemin. On the other hand, as suggested in the past and indicated in the current study, Mb's oxidative power stems from a protein-bound ferric heme whose activity is peroxidase-like: namely, fully dependent on heme iron redox capability. The differences in mechanism of oxidation induced by the two RH proteins are demonstrated schematically in Fig. 9.


Can gas replace protein function? CO abrogates the oxidative toxicity of myoglobin.

Sher EA, Sholto AY, Shaklai M, Shaklai N - PLoS ONE (2014)

Differences in Hb and Mb induced oxidation yield distinct protection mechanisms.In presence of peroxide, ferrous RH are oxidized to their ferric (FeIII) and/or ferryl (FeIV) forms. Upper: Hp binds Hb (ferrous and/or ferric) thereby preventing its release. Lower: Mb heme is retained attached to globin following oxidation in a peroxidase-like form. However, binding of CO to ferrous Mb prevents its oxidation to a ‘peroxidase-like form”.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4128816&req=5

pone-0104075-g009: Differences in Hb and Mb induced oxidation yield distinct protection mechanisms.In presence of peroxide, ferrous RH are oxidized to their ferric (FeIII) and/or ferryl (FeIV) forms. Upper: Hp binds Hb (ferrous and/or ferric) thereby preventing its release. Lower: Mb heme is retained attached to globin following oxidation in a peroxidase-like form. However, binding of CO to ferrous Mb prevents its oxidation to a ‘peroxidase-like form”.
Mentions: The prominent difference between the two mechanisms by which Hb and Mb act, relates to the fact that heme transfer from Mb is negligible in comparison to Hb (Fig. 5). Differences in mechanisms of the two proteins are especially prominent when observing the kinetics of LDL oxidation and its arrest by CO (Fig. 7, main). LDL is oxidized by ferric-Mb at a constant rate, appropriate for enzymatic function. This differs completely from the multistage rate of Hb-induced LDL oxidation (Fig. 7 insert). Despite a common physiological function (oxygen binding to a divalent heme iron), Hb and Mb differ in the mechanism by which they evoke oxidation. Hb oxidative activity results fundamentally from a weakening of the trivalent heme-globin bond [44]. As discussed earlier, ferric-Hb redox activity is manifested by the presence of components that bind hemin strongly, such as LDL [6], [33]. Thus, only a high–affinity globin–binding protein, such as Hp, can efficiently trap hemin. On the other hand, as suggested in the past and indicated in the current study, Mb's oxidative power stems from a protein-bound ferric heme whose activity is peroxidase-like: namely, fully dependent on heme iron redox capability. The differences in mechanism of oxidation induced by the two RH proteins are demonstrated schematically in Fig. 9.

Bottom Line: The main cause of LDL oxidation by Hb was found to be hemin which readily transfers from Hb to LDL.These reactions were fully arrested by CO.The data are interpreted to suit several circumstances, some physiological, such as high muscle activity, and some pathological, such as rhabdomyolysis, ischemia/reperfusion and skeletal muscle disuse atrophy.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

ABSTRACT
Outside their cellular environments, hemoglobin (Hb) and myoglobin (Mb) are known to wreak oxidative damage. Using haptoglobin (Hp) and hemopexin (Hx) the body defends itself against cell-free Hb, yet mechanisms of protection against oxidative harm from Mb are unclear. Mb may be implicated in oxidative damage both within the myocyte and in circulation following rhabdomyolysis. Data from the literature correlate rhabdomyolysis with the induction of Heme Oxygenase-1 (HO-1), suggesting that either the enzyme or its reaction products are involved in oxidative protection. We hypothesized that carbon monoxide (CO), a product, might attenuate Mb damage, especially since CO is a specific ligand for heme iron. Low density lipoprotein (LDL) was chosen as a substrate in circulation and myosin (My) as a myocyte component. Using oxidation targets, LDL and My, the study compared the antioxidant potential of CO in Mb-mediated oxidation with the antioxidant potential of Hp in Hb-mediated oxidation. The main cause of LDL oxidation by Hb was found to be hemin which readily transfers from Hb to LDL. Hp prevented heme transfer by sequestering hemin within the Hp-Hb complex. Hemin barely transferred from Mb to LDL, and oxidation appeared to stem from heme iron redox in the intact Mb. My underwent oxidative crosslinking by Mb both in air and under N2. These reactions were fully arrested by CO. The data are interpreted to suit several circumstances, some physiological, such as high muscle activity, and some pathological, such as rhabdomyolysis, ischemia/reperfusion and skeletal muscle disuse atrophy. It appear that CO from HO-1 attenuates damage by temporarily binding to deoxy-Mb, until free oxygen exchanges with CO to restore the equilibrium.

Show MeSH
Related in: MedlinePlus