The Function of Membrane Integral Pyrophosphatases From Whole Organism to Single Molecule

Abstract

Membrane integral pyrophosphatases (mPPases) are responsible for the hydrolysis of pyrophosphate. This enzymatic mechanism is coupled to the pumping of H+ or Na+ across membranes in a process that can be K+ dependent or independent. Understanding the movements and dynamics throughout the mPPase catalytic cycle is important, as this knowledge is essential for improving or impeding protein function. mPPases have been shown to play a crucial role in plant maturation and abiotic stress tolerance, and so have the potential to be engineered to improve plant survival, with implications for global food security. mPPases are also selectively toxic drug targets, which could be pharmacologically modulated to reduce the virulence of common human pathogens. The last few years have seen the publication of many new insights into the function and structure of mPPases. In particular, there is a new body of evidence that the catalytic cycle is more complex than originally proposed. There are structural and functional data supporting a mechanism involving half-of-the-sites reactivity, inter-subunit communication, and exit channel motions. A more advanced and in-depth understanding of mPPases has begun to be uncovered, leaving the field of research with multiple interesting avenues for further exploration and investigation.

Energy Coupling in Cation-Pumping Pyrophosphatase—Back to Mitchell

“…The Na + ion that occupies site N at high Na + concentrations physically or electrostatically disallows H + passage, explaining why dual Na + and H + specificity is observed with most Na + -PPases only at low Na + levels (Luoto et al, 2013b). A similar explanation assuming two Na + -binding sites was proposed by Holmes et al (2019).…”

The “Water Problem”(sic), the Illusory Pond and Life’s Submarine Emergence—A Review

“…6. Do Fe 3+ polarons in general act to pump anions nano-peristaltically into and/or through the green rust interlayers, as well as pump nutrients through, and toxins and uncooperative molecular waste out of, the system [ 6 , 72 , 315 , 316 , 317 , 318 , 324 , 338 ]?…”

“…If so, can immediate hydrolyses leverage trapping of condensation reactions at neighboring (and oscillating) binding sites (cf. certain pyrophosphatases), i.e., can ‘macromolecular’ green rust effect alternating independent coupling as in the binding change mechanisms that are known to operate in enzymes such as the proton pyrophosphatases [ 72 , 228 , 315 , 316 , 317 , 318 ]?…”

A novel high-throughput screen for identifying lipids that stabilise membrane proteins in detergent based solution

“…They have different folds (from 7 to 16 transmembrane helices), different topologies and different modes of action [32][33][34][35]. M-PPases utilise the pyrophosphate pool to generate electrochemical gradients across membranes in plants, prokaryotes and protist parasites, thereby facilitating their survival during low-energy periods, high-stress conditions and varying osmotic environments [36]. Their potential as drug targets to fight severe parasitic diseases such as malaria, the African sleeping sickness, or toxoplasmosis is currently being investigated [32].…”