Heme-Catalyzed Dityrosine Formation and Serotonin Oxidation in the Presence of Insulin.

Abstract

Insulin resistance and relative insulin deficiency are considered central features in the development of type 2 diabetes mellitus (T2DM). Accumulating evidence suggests that heme contributes to the pathogenesis of this disease. Supporting this view is linking of higher incidence of diabetes with conditions associated with increased extracellular heme due to hemolysis (including thalassemia, hereditary hemochromatosis, transfusion-dependent diseases, etc.). Serotonin (5-HT), which is cosynthesized and stored with insulin in pancreatic β-cells, plays an important role in insulin regulation, and its depletion during the early stages of diabetes has been reported. Elevated levels of dityrosine in the urine of diabetic patients further suggest enhanced oxidative protein modification. Heme-insulin complexes exhibit peroxidase-like activity, thus warranting investigations into the reactive intermediates involved in their catalytic cycle and their consequences for serotonin and insulin oxidation. In this study, using complementary absorption, resonance Raman, EPR, fluorescence, and mass spectrometric analyses, a transient high-valent heme intermediate similar to a Compound I*/Compound ES-like species is identified. It consists of an FeIVO unit along with a protein-derived radical, which is most plausibly localized on a tyrosine residue. This intermediate not only enables oxidation of serotonin but also promotes insulin dimerization and dityrosine cross-linking. These findings provide mechanistic insight into the extracellular redox chemistry of the heme-insulin complex and suggest a possible link between oxidative modification of insulin and serotonin under conditions relevant to oxidative stress.

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BibTeX RIS

BibTeX

@article{pal2026hemecatalyzed,
  title = {{Heme-Catalyzed Dityrosine Formation and Serotonin Oxidation in the Presence of Insulin.}},
  author = {Puja Pal and Madhuparna Roy and Chinmay Dey and Anis Khan and Somdatta Ghosh Dey},
  journal = {JACS Au},
  year = {2026},
  month = sep,
  doi = {10.1021/jacsau.6c00856},
  url = {https://europepmc.org/article/MED/42953618},
  note = {CC BY-NC-ND},
}

RIS

TY  - JOUR
TI  - Heme-Catalyzed Dityrosine Formation and Serotonin Oxidation in the Presence of Insulin.
AU  - Puja Pal
AU  - Madhuparna Roy
AU  - Chinmay Dey
AU  - Anis Khan
AU  - Somdatta Ghosh Dey
PY  - 2026
DA  - 2026/09/01
JO  - JACS Au
DO  - 10.1021/jacsau.6c00856
UR  - https://europepmc.org/article/MED/42953618
AB  - Insulin resistance and relative insulin deficiency are considered central features in the development of type 2 diabetes mellitus (T2DM). Accumulating evidence suggests that heme contributes to the pathogenesis of this disease. Supporting this view is linking of higher incidence of diabetes with conditions associated with increased extracellular heme due to hemolysis (including thalassemia, hereditary hemochromatosis, transfusion-dependent diseases, etc.). Serotonin (5-HT), which is cosynthesized and stored with insulin in pancreatic β-cells, plays an important role in insulin regulation, and its depletion during the early stages of diabetes has been reported. Elevated levels of dityrosine in the urine of diabetic patients further suggest enhanced oxidative protein modification. Heme-insulin complexes exhibit peroxidase-like activity, thus warranting investigations into the reactive intermediates involved in their catalytic cycle and their consequences for serotonin and insulin oxidation. In this study, using complementary absorption, resonance Raman, EPR, fluorescence, and mass spectrometric analyses, a transient high-valent heme intermediate similar to a Compound I*/Compound ES-like species is identified. It consists of an FeIVO unit along with a protein-derived radical, which is most plausibly localized on a tyrosine residue. This intermediate not only enables oxidation of serotonin but also promotes insulin dimerization and dityrosine cross-linking. These findings provide mechanistic insight into the extracellular redox chemistry of the heme-insulin complex and suggest a possible link between oxidative modification of insulin and serotonin under conditions relevant to oxidative stress.
SN  - 2691-3704
ER  -

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