A reaction pathway to compound 0 intermediates in oxy-myoglobin through interactions with hydrogen sulfide and His64

Rodriguez-Mackenzie, Angel D; Arbelo-Lopez, Hector D.; Wymore, Troy; López‐Garriga, Juan

doi:10.1016/j.jmgm.2019.107465

Cited by 2 publications

(8 citation statements)

References 96 publications

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“…In this paramagnetic triplet state, an unpaired electron occupies the central Fe d XZ orbital, while the second unpaired electron is shared between the oxygen atoms bonded to heme. Tis electronic confguration is consistent with the heme compound III [Fe(III)O-O •− , Cpd-III] also known as superoxy-Mbor the Weiss confguration [62] shown in Figure 3(a). Advancing along the reaction coordinate in Figure 3 proton to His64 εδ .…”

Section: Insight Into Sulfmyoglobin Formation Mechanismsupporting

confidence: 76%

“…However, despite this knowledge, the mechanism for sulfheme formation (reaction (1b)), intermediate structure, pH dependence, and the relation to its electronic charge transfer 620 nm band region have remained unresolved. Te report presented here builds upon earlier research [62], examining the infuence of pH on the populations of hemeligand triplets and singlets, as well as the His64 proton relay within the heme pocket. Te results show that oxy-Mb interacting with H 2 S to produce the 5-member ring metaquo-sulfMb (SC) from the Cpd-0 intermediate is energetically favorable by ∆E −69.1 kcal/mol.…”

Section: Introductionmentioning

confidence: 89%

“…Early work [62], conducted at a millisecond scale using stopped-fow spectrophotometry, revealed that, at the more acidic pH of 5.0 during the reaction of oxy-Mb with H 2 S, there is a transition of the Soret band from 414 nm to 416 nm, reaching a maximum absorbance value at 100 ms. Te 2 nm red shift was suggested to be caused by the presence of heme Cpd-0 [Fe(III)OOH]. Hence, the fndings indicate that protonation of the delta nitrogen of His64 εδ (as defned in Scheme 2) enables the migration of the epsilon-located hydrogen, thereby facilitating reaction (1b) and augmenting the intensity of the 622 nm charge transfer transition.…”

Section: Insight Of Ph-dependent Sulfmyoglobin Formationmentioning

confidence: 99%

“…Early results show that the reaction between oxy-Mb and hydrogen sulfde, in the presence of fully protonated His64 εδ , promotes an energetically favorable path (−31.0 kcal/mol) from a heme ligand singlet to a triplet state that stabilizes the heme compound-III [Fe(III)O-O − , Cpd-III], Scheme 1 [62].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, a synchronized higher energy process accompanies the transition from Cpd-III and H 2 S to heme compound 0 [Fe(III)-OOH, Cpd-0]. Tus, Scheme 2 presents a 23.3 kcal/mol barrier coupled with the homolytic cleavage of an S-H bond, following the favorable (−11.2 kcal/ mol) formation of transient Cpd-0 and thiyl radical (HS • ) [62]. However, despite this knowledge, the mechanism for sulfheme formation (reaction (1b)), intermediate structure, pH dependence, and the relation to its electronic charge transfer 620 nm band region have remained unresolved.…”

Section: Introductionmentioning

confidence: 99%

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Mechanistics of pH-Dependent Sulfmyoglobin Formation: Spin Control and His64 Proton Relay

Rodriguez-Mackenzie,

Santos-Velazquez,

Arbelo-Lopez

et al. 2024

Journal of Chemistry

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The chemistry of hydrogen sulfide (H2S) has been directed towards physiologically relevant hemeproteins, including myoglobin, hemoglobin, and other similar proteins. Despite substantial efforts, there remains a need to elucidate the mechanism and identify the species involved in the reaction between oxy-hemeproteins and H2S. Here, we summarize both our experimental data and computational modeling results revealing the mechanisms by which sulfmyoglobin (sulfMb) and sulfhemoglobin (sulfHb) are formed. Our experimental data at pH 7.4 reveal differences in intensity between sulfMb and sulfHb chromophores in the 620 nm charge transfer region. This behavior could be attributed to the incomplete reaction of tetrameric oxy-Hb with H2S, where not all heme groups form sulfheme. The data also show that, for the reaction of oxy-myoglobin (oxy-Mb) and H2S, the 622 nm charge transfer band increases in intensity from a pH of 6.6 to 5.0. This increase is attributed to the presence of the heme pocket distal His64εδ, which is positively charged, resulting in an elevated yield of sulfMb formation compared to the mono-protonated tautomer, His64ε. Computational hybrid QM/MM methods support the conclusion, indicating that oxy-Mb His64εδ (pH 5.0) reacts with H2S in the triplet state, favored by −31.0 kcal/mol over the singlet His64ε (pH 6.6) species. The phenomenon is facilitated by a hydrogen bonding network within the heme pocket, between His64εδ, heme Fe(II)O2, and H2S. The results establish an energetically favored quantitative mechanism to produce sulfMb (−69.1 kcal/mol) from the reactions of oxy-Mb and H2S. Curiously, the mechanism between met-aquo Mb, H2O2, and H2S shows similar reaction pathways and leads to sulfheme formation (−135.3 kcal/mol). The energetic barrier towards intermediate Cpd-0 is the limiting step in sulfheme formation for both systems. ‬Both mechanisms show that the thiyl radical, HS•, is the species attacking the β-β double bond of heme pyrrole B, leading to the sulfheme structure.

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Section: Insight Into Sulfmyoglobin Formation Mechanismsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 89%

Section: Insight Of Ph-dependent Sulfmyoglobin Formationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mechanistics of pH-Dependent Sulfmyoglobin Formation: Spin Control and His64 Proton Relay

Rodriguez-Mackenzie,

Santos-Velazquez,

Arbelo-Lopez

et al. 2024

Journal of Chemistry

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Insights into Sulfhemoglobin Detection: UV-Vis and Fluorescence Spectroscopy Correlations

Santos-Velázquez,

López-Garriga

2023

Journal of Chemistry

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The mechanisms by which drugs and several sulfur chemicals induce sulfhemoglobin formation have not yet been elucidated. However, enzymes producing hydrogen sulfide in mammalian tissues and organs suggest sulfhemoglobin and sulfmyoglobin formation mechanisms are more complex than previously hypothesized. The process involves the interaction of H2S with hemoglobin or myoglobin in the presence of O2 or H2O2 to generate sulfhemoglobin or sulfmyoglobin, respectively. Structurally, the sulfheme product chromophore is a covalent heme modification. This modification involves the incorporation of one sulfur atom within carbon atoms to form a sulfur-carbons ring moiety across the β-β double bond of heme pyrrole B, which shows a characteristic optical band around 623 nm and 618 nm for sulfhemoglobin and sulfmyoglobin, respectively. The results show a linear correlation between the sulfHb electronic charge transfer transition at 623 nm and the emission wavelength of 460 nm upon Soret excitation at 420 nm. The data show no such linear relationship for oxy-Hb or met-aquo Hb. This new approach allows us to measure from 0.02% to 13.5% sulfhemoglobin in mixtures of met-aquo hemoglobin and oxy-hemoglobin. Although additional work is needed, the results suggest that simultaneously monitoring sulfHb electronic transition at 623 nm and emission wavelength at 460 nm upon Soret excitation at 420 nm is a powerful technique to determine the percentage of sulfhemoglobin in blood. The data and techniques presented indicate that fluorescence spectroscopy coupled with UV-vis spectroscopy provides a fast and accurate method for detecting sulfhemoglobin in the blood, facilitating the diagnosis of sulfhemoglobinemia in patients.

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A reaction pathway to compound 0 intermediates in oxy-myoglobin through interactions with hydrogen sulfide and His64

Cited by 2 publications

References 96 publications

Mechanistics of pH-Dependent Sulfmyoglobin Formation: Spin Control and His64 Proton Relay

Mechanistics of pH-Dependent Sulfmyoglobin Formation: Spin Control and His64 Proton Relay

Insights into Sulfhemoglobin Detection: UV-Vis and Fluorescence Spectroscopy Correlations

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