bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2024–11–24
two papers selected by
Gavin McStay, Liverpool John Moores University



  1. Photochem Photobiol Sci. 2024 Nov 22.
      Basic concepts and theoretical foundations of broken symmetry (BS) and post BS methods for strongly correlated electron systems (SCES) such as electron-transfer (ET) diradical, multi-center polyradicals with spin frustration are described systematically to elucidate structures, bonding and reactivity of the high-valent transition metal oxo bonds in metalloenzymes: photosystem II (PSII) and cytochrome c oxidase (CcO). BS hybrid DFT (HDFT) and DLPNO coupled-cluster (CC) SD(T0) computations are performed to elucidate electronic and spin states of CaMn4Ox cluster in the key step for oxygen evolution, namely S4 [S3 with Mn(IV) = O + Tyr161-O radical] state of PSII and PM [Fe(IV) = O + HO-Cu(II) + Tyr161-O radical] step for oxygen reduction in CcO. The cycle of water oxidation catalyzed by the CaMn4Ox cluster in PSII and the cycle of oxygen reduction catalyzed by the CuA-Fea-Fea3-CuB cluster in CcO are examined on the theoretical grounds, elucidating similar concerted and/or stepwise proton transfer coupled electron transfer (PT-ET) processes for the four-electron oxidation in PSII and four-electron reduction in CcO. Interplay between theory and experiments have revealed that three electrons in the metal sites and one electron in tyrosine radical site are characteristic for PT-ET in these biological redox reaction systems, indicating no necessity of harmful Mn(V) = O and Fe(V) = O bonds with strong oxyl-radical character. Implications of the computational results are discussed in relation to design of artificial systems consisted of earth abundant transition metals for water oxidation.
    Keywords:  Broken symmetry; Cytochrome c oxidase; Photosystem II; Proton transfer coupled electron transfer; Strongly correlated electron systems
    DOI:  https://doi.org/10.1007/s43630-024-00648-w
  2. Redox Biol. 2024 Nov 10. pii: S2213-2317(24)00404-X. [Epub ahead of print]78 103426
      Mitochondria are essential to cellular function as they generate the majority of cellular ATP, mediated through oxidative phosphorylation, which couples proton pumping of the electron transport chain (ETC) to ATP production. The ETC generates an electrochemical gradient, known as the proton motive force, consisting of the mitochondrial membrane potential (ΔΨm, the major component in mammals) and ΔpH across the inner mitochondrial membrane. Both ATP production and reactive oxygen species (ROS) are linked to ΔΨm, and it has been shown that an imbalance in ΔΨm beyond the physiological optimal intermediate range results in excessive ROS production. The reaction of cytochrome c oxidase (COX) of the ETC with its small electron donor cytochrome c (Cytc) is the proposed rate-limiting step in mammals under physiological conditions. The rate at which this redox reaction occurs controls ΔΨm and thus ATP and ROS production. Multiple mechanisms are in place that regulate this reaction to meet the cell's energy demand and respond to acute stress. COX and Cytc have been shown to be regulated by all three main mechanisms, which we discuss in detail: allosteric regulation, tissue-specific isoforms, and post-translational modifications for which we provide a comprehensive catalog and discussion of their functional role with 55 and 50 identified phosphorylation and acetylation sites on COX, respectively. Disruption of these regulatory mechanisms has been found in several common human diseases, including stroke and myocardial infarction, inflammation including sepsis, and diabetes, where changes in COX or Cytc phosphorylation lead to mitochondrial dysfunction contributing to disease pathophysiology. Identification and subsequent targeting of the underlying signaling pathways holds clear promise for future interventions to improve human health. An example intervention is the recently discovered noninvasive COX-inhibitory infrared light therapy that holds promise to transform the current standard of clinical care in disease conditions where COX regulation has gone awry.
    DOI:  https://doi.org/10.1016/j.redox.2024.103426