Lipid A biosynthesis lauroyl acyltransferase (MsbB) (MsbB)

Lipid A biosynthesis lauroyl acyltransferase, commonly known as MsbB, is a critical enzyme in the late stages of Lipid A (endotoxin) biosynthesis in Gram-negative bacteria such as Escherichia coli and Salmonella typhimurium. It catalyzes the transfer of a laurate (C12) fatty acid chain to the KDO2-lipid IVA precursor, a step essential for the formation of the mature, hexa-acylated Lipid A structure (UniProt P24205). This hexa-acylated form is the primary trigger for the human TLR4/MD2 receptor complex, which initiates the potent inflammatory response characteristic of Gram-negative sepsis (PubMed: 11544351). In the context of drug development and biotechnology, MsbB is a primary target for bacterial attenuation. Deletion of the msbB gene results in the production of penta-acylated Lipid A, which possesses significantly reduced endotoxic activity—often 1,000 to 10,000-fold less than wild-type LPS—while maintaining the bacteria's ability to colonize tissues (PubMed: 9234695). This strategy was famously employed in the development of VNP20009, a genetically modified Salmonella strain designed for tumor-targeted therapy, where MsbB deficiency allowed for safe systemic administration in cancer patients by minimizing the risk of septic shock (PubMed: 12124317).

Other names

LpxLLauroyl acyltransferaseLipid A biosynthesis protein MsbBKDO2-lipid IVA lauroyltransferase

Deletion or inhibition of MsbB prevents the addition of the terminal myristoyl or lauroyl group to Lipid A, resulting in a penta-acylated rather than hexa-acylated structure. This modification significantly reduces the ability of the lipopolysaccharide (LPS) to trigger Toll-like receptor 4 (TLR4) signaling, thereby decreasing the induction of pro-inflammatory cytokines like TNF-alpha and reducing systemic toxicity (UniProt P24205; PubMed: 10556328).