Bacterial Fdx-supported, HscBA-assisted Isc iron-sulfur cluster assembly

A bacterial Isc mechanism for iron-sulfur cluster assembly and transfer supported by Isc ferredoxin and the dedicated HscBA cycle. IscS mobilizes cysteine sulfur as a persulfide and supplies IscU, the transient cluster scaffold. Reduced Isc ferredoxin supplies reducing equivalents; HscB recruits IscU to the HscA ATPase, coupling ATP hydrolysis to cluster release and delivery. An optional IscA carrier branch supports condition- and client-dependent iron or cluster handling. Reduced anaerobic ISC implementations and scaffold-suppressor bypasses are comparative boundary cases outside the encoded Fdx-supported, HscBA-assisted profile; their altered requirements are not additional modeled variants here. IscR regulation, CyaY and IscX modulation, upstream iron and reductant supply, mitochondrial ISC, and the separate Suf and Nif systems lie outside this mechanism.

The modeled capacity is the canonical Fdx-supported, HscBA-assisted route. IscS, IscU, Fdx, HscB and HscA are required for that profile, not asserted universally necessary for all ISC-dependent synthesis. In E. coli lacking SUF, loss of Fdx can be tolerated anaerobically; the same primary study retains a requirement for wild-type IscS, IscU, HscB and HscA in that assay. Separate IscU suppressor substitutions partially bypass HscBA. These are distinct condition/genotype boundaries, not proof that unmodified IscSU alone supplies every client. Alternative electron-carrier identity remains unresolved. IscA is optional at this nascent-cluster/transfer boundary, without claiming dispensability for all aerobic clients or elevated-oxygen Azotobacter growth. Bacteria is a distribution envelope, not universal conservation. The reviewed panel samples E. coli, P. putida and A. vinelandii within Gammaproteobacteria; it does not establish experimentally complete coverage across bacterial phyla. The Azotobacter sequences match the original AF010139 deposit; DJ116 sequence origin and subsequent DJ-derived experimental strains are distinguished in the member map. Five Azotobacter representatives support the canonical profile. Housekeeping IscA O31271 remains a reviewed comparator: broad binding and native participation do not establish its exact cluster-delivery chemistry, and NifIscA experiments are not transferred to it. Evidence strength differs by role and species. Native Azotobacter Fdx redox measurements, specific ISC signatures and depletion phenotypes support an inferred donor role by comparison with E. coli mechanism. Its native donor/acceptor chain is not reconstituted. In the Azotobacter HscBA assay, apo-Fdx is a cluster recipient, not evidence of electron donation. KT2440 roles also rely on comparative inference. A supported/inferred capacity profile must be distinguished from an assay-only cognate electron-relay profile. Available iron, L-cysteine, ATP and reduced ferredoxin are inputs. The physiological iron donor and loading order remain unresolved; reductase/reduced-ferredoxin supply is upstream. IscA is not the sole asserted iron source, and no fixed IscU-to-IscA ordering is encoded. Purified IscA iron donation and intact cluster delivery are distinct molecular claims. HscA family/subfamily descriptors are alternative classifications of one role, not two required proteins. HscA contributes ATP hydrolysis coupled to IscU transfer; HscB contributes ATPase activation and scaffold recruitment. Neither role automatically establishes generic folding/refolding. Broad Hsp70, J-domain, ferredoxin or IscU/SufU-family membership alone is insufficient. Family reviews retain unresolved universal function scopes, while representative-specific functions and cognate interfaces ground this module.