Despite being soft, squishy, and slow-moving, sea cucumbers (Class Holothuroidea) are surprisingly tough. They scavenge in harsh, rapidly changing conditions on the ocean floor, under the constant threat of toxic bacteria. To protect themselves against predators and pathogens alike, sea cucumbers produce defensive toxins called saponins, as do their close cousins, starfish. However, new research finds that sea cucumbers are the only echinoderms—and among the only animals on Earth—that produce chemicals called triterpenoid saponins, which don’t poison the sea cucumbers themselves thanks to their unique metabolic pathways.
A study published Monday (June 27) in Nature Chemical Biology finds that sea cucumbers have evolved a way to synthesize these saponins with different enzymes than those used by their echinoderm cousins and the vast majority of other animals. In doing so, they’ve evolved a mechanism that makes them immune to their own saponins.
“I think [the study] is really impressive,” Annalisa Pinsino, a marine biologist at the Institute of Translational Pharmacology in Rome who was not involved in the study, tells The Scientist. She says that, since sea cucumbers lack any adaptive immunity and must rely on their innate defenses to survive, “it’s not so surprising that . . . sea cucumbers evolved something special” to defend themselves.
Previously, scientists knew that sea cucumbers produced triterpenoid saponins, which are more commonly found in plants than in animals. These chemicals bind to cholesterol molecules on cell membranes and rapidly cause death. In the new study, the researchers found that the sea cucumbers don’t produce cholesterol and have very little of it on their membranes, which allows them to remain unfazed by saponins. The researchers, led by Ramesha Thimmappa, a biologist at Amity University Uttar in Noida, India, who had previously worked with plant triterpenoids, wanted to find out more about how and why the sea cucumber made these rare compounds.
Sea star saponins are steroid-based. Triterpenoids and sterols are derived from similar molecules, and the molecular pathways to produce both involve enzymes called oxidosqualane cyclases (OSCs). Wanting to learn more about how these pathways differed among echinoderms, the researchers searched the human, sea urchin, and sea star genomes for an OSC called lanosterol synthase (LSS), which is important for sterol—including cholesterol—production in most animal species and for saponin production in starfishes. To their surprise, the researchers found that sea cucumbers lack the gene that produces LSS entirely, as well as three other enzymes that allow other species to make sterols. Instead, the sea cucumber genome contains two other genes for OSCs.
To investigate further, the researchers cloned and transferred OSC genes from two sea cucumber species (Apostichopus japonicus and Parastichopus parvimensis) into yeast that lacked the gene for LSS. Both of the genes failed to restore the yeast’s full function, again indicating that the genes weren’t coding for LSS. The team discovered that the cucumber OSC genes produced two sterol-like molecules, both of which were involved in triterpenoid production. These molecules also converted compounds into the cholesterol-like molecules that are present in the sea cucumber cell membranes. The molecules function similarly to cholesterol, but their differences help the animals avoid poisoning themselves with saponins. In another experiment, the researchers inserted mutated copies of the sea cucumber OSC genes into yeast, finding that two separate mutations affecting a single amino acid coded by the LSS gene are responsible for the altered function of both sea cucumber OSC enzymes.
Having two OSC-coding genes, neither of which are for LSS, is “highly exceptional in the animal kingdom,” says Thimmappa. He adds that sea cucumbers are the only known animals to have two OSC-coding genes but not make their own cholesterol.
Sea cucumber-derived extracts, especially saponins, are highly valued for medicinal purposes. Saponins are used as immune adjuvants in vaccines, says Thimmappa, and may have anti-inflammatory and anticancer properties. He says he hopes that, in the future, his work can help in devising ways to derive these compounds from plants and yeasts without grinding up sea cucumbers, which are endangered in some parts of the world.
And it’s vital to conserve these creatures, Thimmappa says, noting that they serve similar functions to earthworms in soil. They clean and clear debris and detritus from on the ocean floor and excrete oxygen-rich sand. “Sea cucumbers are so important for the environment,” he says.