Invited review: Quantifying proton exchange from chemical reactions - Implications for the biochemistry of metabolic acidosis

Given that the chemistry of lactate production disproves the existence of a lactic acidosis, there is a need to further reveal and explain the importance of the organic and computational chemistry of pH dependent competitive cation fractional (~) proton (H+) exchange (~H+e). An additional importance of this knowledge is that it could potentially contradict the assumption of the Stewart approach to the physico-chemical theory of acid-base balance. For example, Stewart proposed that chemical reaction and pH dependent H+ dissociation and association do not directly influence the pH of cellular and systemic body fluids. Yet at the time of Stewart's work, there were no data that quantified the H+ exchange during chemical reactions, or from pH dependent metabolite H+ association or dissociation. Consequently, the purpose of this review and commentary was three-fold; 1) to provide explanation of pH dependent competitive cation ~H+e exchange; 2) develop a model of and calculate new data of substrate flux in skeletal muscle during intense exercise; and 3) then combine substrate flux data with the now known ~H+e from chemical reactions of non-mitochondrial energy catabolism to quantify chemical reaction and metabolic pathway ~H+e. The results of purpose 3 were that ~H+ release for the totality of cytosolic energy catabolism = −187.2 mmol·L−1, where total glycolytic ~H+te = −85.0 mmol·L−1. ATP hydrolysis had a ~H+te = −43.1 mmol·L−1. Lactate production provided the largest metabolic ~H+ buffering with a ~H+te = 44.5 mmol·L−1. The total ~H+ release to La ratio = 4.25. The review content and research results of this manuscript should direct science towards new approaches to understanding the cause and source of H+e during metabolic acidosis and alkalosis. •The prior explanation of the cause of metabolic acidosis; that of a lactic acidosis, has been challenged repeatedly since the late 1970s.•More recently, empirically supported falsification of the construct has gained considerable international acceptance and there is an on-going readjustment of this paradigm that explains metabolic acidosis.•Consequently, there is a need to apply foundation principles of computational chemistry to the known organic chemistry of chemical reactions to improve our understanding of the exchange of protons (H+) in chemical reactions.•Further, it is important to quantify the capacity for H+ exchange to ascertain the relevance of these events to cellular and systemic acid-base balance.•This