The suicide inactivation mechanism of tyrosinase acting on its substrates has been studied. The kinetic analysis of the proposed mechanism during the transition phase provides explicit analytical expressions for the concentrations of o-quinone against time. The electronic, steric and hydrophobic effects of the substrates influence the enzymatic reaction, increasing the catalytic speed by three orders of magnitude and the inactivation by one order of magnitude. To explain the suicide inactivation, we propose a mechanism in which the enzymatic form E(ox) (oxy-tyrosinase) is responsible for such inactivation. A key step might be the transfer of the C-1 hydroxyl group proton to the peroxide, which would act as a general base. Another essential step might be the axial attack of the o-diphenol on the copper atom. The rate constant of this reaction would be directly related to the strength of the nucleophilic attack of the C-1 hydroxyl group, which depends on the chemical shift of the carbon C-1 (delta(1)) obtained by (13)C-NMR. Protonation of the peroxide would bring the copper atoms together and encourage the diaxial nucleophilic attack of the C-2 hydroxyl group, facilitating the co-planarity with the ring of the copper atoms and the concerted oxidation/reduction reaction, and giving rise to an o-quinone. The suicide inactivation would occur if the C-2 hydroxyl group transferred the proton to the protonated peroxide, which would again act as a general base. In this case, the co-planarity between the copper atom, the oxygen of the C-1 and the ring would only permit the oxidation/reduction reaction on one copper atom, giving rise to copper(0), hydrogen peroxide and an o-quinone, which would be released, thus inactivating the enzyme.

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Objectives: To investigate if depression risk modifies the association between frailty and mortality in older adults. Design: Ongoing cohort study. Setting: Albacete city, Spain Participants: Eight hundred subjects, 58.8% women, over 70 years of age from the Frailty and Dependence in Albacete (FRADEA) study. Measurements: Frailty phenotype, Geriatric Depression Scale (GDS), comorbidity, disability, and drug use were collected at baseline. Six groups were categorized: (G1: non-frail/no depression risk; G2: non-frail/depression risk; G3: prefrail/no depression risk; G4: prefrail/depression risk; G5: frail/no depression risk; and G6: frail/depression risk). Mean follow-up was 2542 days (SD 1006). GDS was also analyzed as a continuous variable. The association between frailty and depression risk with 10-year mortality was analyzed. Results: Mean age was 78.5 years. Non-frail was 24.5%, prefrail 56.3%, frail 19.3%, and 33.5% at depression risk. Mean GDS score was 3.7 (SD 3.2), increasing with the number of frailty criteria (p < 0.001). Ten-year mortality rate was 44.9%. Mortality was 21.4% for the non-frail, 45.6% for the prefrail, and 72.7% for the frail participants, 56% for those with depression risk, and 39.3% for those without depression risk. Mean survival times for groups G1 to G6 were, respectively, 3390, 3437, 2897, 2554, 1887, and 1931 days. Adjusted mortality risk was higher for groups G3 (HR 2.1; 95% confidence interval (CI) 1.4–3.1), G4 (HR 2.5; 95% CI 1.7–3.8), G5 (HR 3.8; 95% CI 2.4–6.1), and G6 (HR 4.0; 95% CI 2.6–6.2), compared with G1 (p < 0.001). Interaction was found between frailty and depression risk, although they were independently associated with mortality. Conclusions: Depression risk increases mortality risk in prefrail older adults but not in non-frail and frail ones. Depression should be monitored in these older adults to optimize health outcomes. Factors modulating the relationship between frailty and depression should be explored in future studies.

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