Leukaemia Drug Homoharringtonine's Backbone Is Made at the Root Tip: 6 Enzymes Identified

The team of Elizabeth Sattely at Stanford University in the United States has uncovered nearly the entire biosynthetic pathway to cephalotaxine (CET), the core scaffold of the anti-leukaemia drug homoharringtonine (HHT). HHT, a plant-derived compound that inhibits protein translation, has been approved by the U.S. FDA for chronic myeloid leukaemia and is also widely used as a tool in ribosome profiling research. Commercial production, however, depends on semisynthesis from CET extracted from plants of the genus Cephalotaxus, which are endangered.

7 intermediates and 6 enzymes: the scaffold forms at the root tip

The researchers traced the pathway by feeding stable isotope-labelled precursors and pairing untargeted metabolomics with transcriptomics. They confirmed that CET is synthesised only at the growing root tips, but that CET and HHT accumulate throughout the plant. They found 7 pathway intermediates and 6 enzymes. Cytochrome P450s, an atypical short-chain dehydrogenase, a 2-oxoglutarate-dependent dioxygenase and others remove carbons and build the five-ring scaffold, producing cephalotaxinone, which appears to be the direct precursor of CET.

The researchers proposed a whole-plant collaboration model in which cephalotaxinone made at the root tip is carried to other parts of the plant and completed into HHT. However, the enzymes of the final steps leading to CET and HHT were not confirmed in this study, and production in a heterologous host is the next task.