Archaeal enzymes linked to complex life make cyclical terpenes

One of biology’s biggest questions is how the first eukaryotic cell — the kind of cell that makes up plants, animals and fungi — arose from simpler ancestors. The leading idea is that a union between an archaeon and a bacterium created the first eukaryote, and modern relatives of that archaeal partner belong to a group called Asgardarchaeota, probably near the Heimdallarchaeia clade. But we still know very little about the distinctive biochemistry of these microbes and how it might have helped shape the rise of complex cells. In work led by corresponding author Paula V. Welander, researchers set out to explore whether Asgardarchaeota produce a class of molecules called cyclic terpenoids. These compounds are common in many forms of life and can perform structural and signaling roles. By looking across genomes and predicting the shapes of the proteins those genomes encode, the team searched for the enzymatic machinery that would be needed to build cyclic terpenoids in modern Asgard lineages, aiming to link gene content to biochemical capability in these key microbes.

The study combined phylogenomics with structural prediction to search Asgard genomes for enzymes known to make diterpenoids. Phylogenomics — the comparison of many genes across related organisms — flagged candidate genes in two Asgard clades, Hodarchaeales and Kariarchaeaceae, as encoding diterpenoid cyclases. Structural prediction supported those assignments by showing the candidate proteins had shapes consistent with cyclase activity. To test whether the proteins were functional, the researchers performed in vitro experiments, extracting or expressing the enzymes and supplying the substrate geranylgeranyl pyrophosphate. In those tests the enzymes converted geranylgeranyl pyrophosphate into a bicyclic product, halimadienyl pyrophosphate. The paper also notes that halimadienyl nucleosides have previously been shown to mediate intracellular persistence of Mycobacterium tuberculosis in host endosomes, and suggests the terpenoid products might play related roles in Asgardarchaeota.

Finding functional diterpenoid cyclases in Asgardarchaeota helps fill a gap in our understanding of what these microbes can do chemically, and it gives researchers concrete biochemical targets to study in the context of early cellular evolution. Knowing that Hodarchaeales and Kariarchaeaceae can make bicyclic halimadienyl pyrophosphate connects Asgard biology to broader metabolic themes found in other microbes, and it raises questions about the ecological and cellular roles of those compounds in archaeal cells. Because halimadienyl nucleosides are implicated in the intracellular persistence of Mycobacterium tuberculosis, the discovery also highlights a biochemical link that may be worth exploring for its functional parallels, though direct relationships between Asgard terpenoids and pathogenic behavior are not claimed. Overall, characterizing these enzymes provides a clearer picture of the molecular toolkit available to the archaeal relatives of the first eukaryote and opens new avenues for research into the chemistry that accompanied the origin of complex life.