Tracking acetate through a journey of living world: Evolution as alternative cellular fuel with potential for application in cancer therapeutics

Abstract Acetate is a short chain fatty acid, comprising carbon, hydrogen and oxygen (C 2 H 3 O 2 − ), which has emerged as a key alternative fuel for cellular metabolism. Beginning its voyage from the abiotic atmosphere, acetate has contributed to the physiology of both prokaryotes and eukaryotes. The main role of acetate includes its contribution to the global carbon cycle, bioenergetic and biosynthetic metabolic processes. Based on the ability to produce and consume acetate, organisms are categorized as acetogenic, acetate-consumers or both depending on their genetic make-up of the metabolizing enzymes' repertoire. The key molecules implicated in utilization and production of acetate include, but not limited to, monocarboxylate transporters, enzymes regulating acetate utilization like AMP-forming Acetyl CoA synthetase (ACS-AMP), Acyl-CoA short chain synthetase 1, 2 (ACSS1, 2), and production like Acetate kinase (ACK)/Phosphotransacetylase (PTA), ADP-forming acetyl CoA synthetase (ACS-ADP), Pyruvate:ferredoxin oxidoreductase, histone deacetylase and acetyl CoA hydrolase. These enzymes are utilized by the acetate homeostasis machinery in a variable manner. As malignant cells also display highly upregulated metabolic processes for rapid energy generation, they display an immense need for alternative carbon sources to fuel their metabolism. Tumor cells display over expression of transporters and enzymes implicated in their acetate utility machinery. This review also highlights mechanisms of the pro and antitumor potential of acetate depending on the genetic and metabolic makeup of neoplastic cells. The present review is a comprehensive compilation of the available literature with respect to the role of acetate in the biology of living organisms and its potential for being maneuvered in anticancer therapeutics.