Terpenes, hormones and life: isoprene rule revisited.

Abstract

The year 2019 marks the 80th anniversary of the 1939 Nobel Prize in Chemistry awarded to Leopold Ruzicka (1887-1976) for work on higher terpene molecular structures, including the first chemical synthesis of male sex hormones. Arguably his crowning achievement was the 'biogenetic isoprene rule', which helped to unravel the complexities of terpenoid biosynthesis. The rule declares terpenoids to be enzymatically cyclized products of substrate alkene chains containing a characteristic number of linear, head-to-tail condensed, C5 isoprene units. The number of repeat isoprene units dictates the type of terpene produced (i.e., 2, monoterpene; 3, sesquiterpene; 4, diterpene, etc.). In the case of triterpenes, six C5 isoprene units combine into C30 squalene, which is cyclized into one of the signature carbon skeletons from which myriad downstream triterpenoid structures are derived, including sterols and steroids. Ruzicka also had a keen interest in the origin of life, but the pivotal role of terpenoids has generally been overshadowed by nucleobases, amino acids, and sugars. To redress the balance, we provide a historical and evolutionary perspective. We address the potential abiotic generation of isoprene, the crucial role that polyprene terpenoids played in early membranes and cellular life, and emphasize that endocrinology from microbes to plants and vertebrates is firmly grounded on Ruzicka's pivotal insights into the structure and function of terpenes. A harmonizing feature is that all known lifeforms (including bacteria) biosynthesize triterpenoid substances that are essential for cellular membrane formation and function, from which signaling molecules such as steroid hormones and cognate receptors are likely to have evolved.