Kdo2-lipid A biosynthesis (Raetz pathway)

The constitutive nine-enzyme Raetz pathway that builds Kdo2-lipid A, the minimal essential lipopolysaccharide anchor, at the cytoplasmic face of the Gram-negative inner membrane. LpxA reversibly transfers an (R)-3-hydroxyacyl chain from acyl carrier protein (ACP) to UDP-GlcNAc; the zinc deacetylase LpxC then irreversibly removes the N-acetyl group, the committed step that sets pathway flux. LpxD adds the second (R)-3-hydroxyacyl chain, LpxH cleaves part of the UDP-diacylglucosamine pool to lipid X, LpxB condenses lipid X with UDP-diacylglucosamine to the beta-1',6-linked disaccharide, and LpxK phosphorylates the 4' position to give lipid IVA. The bifunctional Kdo transferase WaaA adds two Kdo residues from CMP-Kdo, and the late acyltransferases LpxL and LpxM add laurate and myristate to the Kdo2-lipid IVA acceptor to give hexa-acylated Kdo2-lipid A. Flux is set at LpxC by FtsH-mediated proteolysis tuned by the adaptor LapB and the anti-adaptor YejM (PbgA), represented here as an optional regulatory part rather than as pathway chemistry.

Boundary. The module starts at the LpxA acyl transfer onto UDP-GlcNAc and ends at Kdo2-lipid A. Substrate supply is upstream and outside the module: UDP-GlcNAc (shared with peptidoglycan precursor synthesis, see MODULE:peptidoglycan_precursor_biosynthesis), (R)-3-hydroxymyristoyl-ACP from type II fatty acid synthesis (where FabZ competes with LpxA for the same pool), and CMP-Kdo from MODULE:kdo_biosynthesis, whose KdsB product is consumed by the WaaA step modelled here. Core oligosaccharide assembly, MsbA flipping, O-antigen ligation and Lpt-mediated transport to the outer membrane (MODULE:bacterial_lps_transport) are downstream; inducible lipid A modification (e.g. MODULE:lipid_a_l_arabinose_modification) and host recognition of the product (MODULE:tlr4_md2_lps_signaling) are separate modules. Committed step. LpxA is the first pathway-specific reaction but is reversible and thermodynamically unfavourable (Keq about 0.01, PMID:8366124), so commitment occurs at the irreversible LpxC deacetylation. This is recorded on the lpxC_step node and is the reason the regulatory part targets that step and no other. Regulation vs parts. FtsH, LapB (YciM) and YejM (PbgA/LapC) do no lipid A chemistry: they set the steady-state amount (and, for LapB, the activity) of LpxC. They are therefore modelled as a single optional REGULATORY_STEP part connected to lpxC_step by NEGATIVELY_REGULATES, not as steps in the reaction chain. FabZ, PldA/FadD-derived acyl-CoA signalling, the Rod complex and Lpt/OM-derived inputs described in PMID:42264091 are left out entirely: their link to LpxC abundance is genetic or indirect and belongs in the phospholipid/peptidoglycan modules. LapB has two documented activities on LpxC - adaptor-mediated delivery to FtsH and direct allosteric inhibition of deacetylase activity (PMID:38635633). Only the adaptor role is given a GO molecular function here; the inhibitory activity is recorded in role_description and notes because an in vivo contribution has not been established. Grounding. Participants are concrete Escherichia coli K-12 gene products because the reviewed scope is the E. coli pathway; PANTHER families are given alongside each exemplar so the steps can be reused for other Gram-negative lineages. LpxH is not universal among Gram-negative bacteria (PMID:12045108 notes its absence from some Gram-negative genomes, implying another enzyme for this step), but no alternative is asserted here because no second implementation was reviewed. Likewise the cold-shock-induced LpxL paralogue LpxP, which adds palmitoleate in place of laurate at low temperature (PMID:12045108), is outside this constitutive module and is not modelled as a variant of the lpxL_step. No cytoplasm/cytosol term is asserted at module level; per-step locations follow the GOA cellular-component annotations of each enzyme.