Tripping the light fantastic in membrane redox biology: linking dynamic structures to function in ER electron transfer chains

Abstract

How the dynamics of proteins assist catalysis is a contemporary issue in enzymology. In particular, this holds true for membrane‐bound enzymes, where multiple structural, spectroscopic and biochemical approaches are needed to build up a comprehensive picture of how dynamics influence enzyme reaction cycles. Of note are the recent studies of cytochrome P450 reductases (CPR)–P450 (CYP) endoplasmic reticulum redox chains, showing the relationship between dynamics and electron flow through flavin and haem redox centres and the impact this has on monooxygenation chemistry. These studies have led to deeper understanding of mechanisms of electron flow, including the timing and control of electron delivery to protein‐bound cofactors needed to facilitate CYP‐catalysed reactions. Individual and multiple component systems have been used to capture biochemical behaviour and these have led to the emergence of more integrated models of catalysis. Crucially, the effects of membrane environment and composition on reaction cycle chemistry have also been probed, including effects on coenzyme binding/release, thermodynamic control of electron transfer, conformational coupling between partner proteins and vectorial versus ‘off pathway’ electron flow. Here, we review these studies and discuss evidence for the emergence of dynamic structural models of electron flow along human microsomal CPR–P450 redox chains.

Molecular Lego of Human Cytochrome P450: The Key Role of Heme Domain Flexibility for the Activity of the Chimeric Proteins

“…In order to recapitulate and provide adequate contextualization for our data, we can refer to the relationship between the cytochrome P450 reductase (CPR) dynamics, its reactions cycle [ 64 ], and the events required for catalysis to occur. Two models have been proposed for CPR dynamics linked to catalysis.…”

“…Two models have been proposed for CPR dynamics linked to catalysis. In the first model CPR moves from a more ‘open’ state to a ‘closed’ state when reduced with one equivalent of NADPH and upon reduction by a second NADPH equivalent, CPR is predominantly in an ‘open’ state compatible with electron transfer to P450 [ 64 ]. In the second model, the enzyme is ‘closed’ in the oxidized coenzyme free state and upon reduction with NADPH, CPR opens, and electrons can be passed to P450 [ 64 ].…”

Solvent-slaved protein motions accompany proton coupled electron transfer reactions catalysed by copper nitrite reductase

“…Enzyme catalysed electron transfer reactions are ubiquitous in biology and are often coupled to protein conformational change or additional chemical steps. 1,2 An example of a chemical event that is frequently linked to electron transfer reactions is proton transfer. The transfer of an electron and a proton together (either by a sequential or a concerted mechanism) is referred to as proton coupled electron transfer (PCET).…”

Mechanisms of Hypercapnia-Induced Endoplasmic Reticulum Dysfunction

“…Whether hypercapnia affects ER-resident oxidoreductases and protein disulfide isomerases (such as Ero1, PDI, and OSM1) is currently unknown and needs further investigation. Moreover, the ER, redox reactions and iron metabolism are tightly linked together (Banhegyi et al, 2012;Andreini et al, 2018;Hedison and Scrutton, 2019). Therefore, the role of the iron-proteome in CO 2 sensing and hypercapnia-induced ER oxidation status changes needs further attention.…”