![iub chemistry mestrenova iub chemistry mestrenova](https://ars.els-cdn.com/content/image/1-s2.0-S0141813019388920-sc1.jpg)
Only Pia has been biochemically and functionally characterized as an Fe III-ferrichrome uptake transporter in Spn, with the physiological Fe substrates for the other systems unclear or unknown. pneumoniae: although other streptococci encode FeoB, the model serotype 2 Spn strain used here, S. It is unknown whether Fe II can be imported by S. Three ABC transporters are known or projected to transport Fe III-siderophores, Pit, Pia, Piu, and two additional iron substrate binding proteins may play an accessory role in Fe uptake. The genome of Spn does encode several cell membrane-tethered substrate binding proteins (SBPs) coupled to ATP-dependent active transport systems, as classical ATP-binding cassette (ABC) transporters. No siderophore biosynthesis pathway has been identified in the Spn genome and thus it is widely believed that Spn is unable to synthesize siderophores. ĭespite what appears to be a low Fe requirement, Spn still faces the challenge of acquiring sufficient Fe from the host to meet cellular needs, which becomes particularly critical when Spn moves from the upper airway to sterile sites in the lung, cardiac tissue and the bloodstream to cause invasive disease. Fe homeostasis in Spn is instead controlled in part by RitR, an orphan response regulator that senses reactive oxygen species (ROS) generated by cell-excess Fe II and endogenous hydrogen peroxide generated by pyruvate oxidase (SpxB) and lactate oxidase (LctO) when this facultative anaerobe respires on molecular oxygen. In fact, Spn has very few known Fe-requiring enzymes and lacks Fur and IdeR, well-characterized global Fe-uptake regulators associated with many Gram-positive and Gram-negative bacteria. Spn is a Gram-positive lactic acid bacterium that lacks a TCA cycle and a respiratory electron transfer chain, and thus is characterized by a relatively low cellular Fe quota. Streptococcus pneumoniae (Spn) is a commensal inhabitant of the upper respiratory tract in humans, but upon invasion of other sterile tissues becomes a formidable pathogen that causes millions of infections worldwide, many with increasing occurrence of antibiotic resistance. This process of iron acquisition enhances the virulence of many bacterial pathogens during infections, and has been extensively investigated for decades due to its physiological and therapeutic importance. In response to low iron bioavailability, many pathogens synthesize and secrete low molecular weight, high-affinity iron chelators, called siderophores, to scavenge ferric iron (Fe III) from the host environment and subsequently import Fe III-siderophores via specialized high-affinity uptake systems. Host cells deplete labile iron in the serum by secreting high affinity iron-binding proteins such as transferrin, lactoferrin, and ferritin thus inducing widespread iron starvation in invading pathogens. The sequestration of this essential nutrient from bacterial invaders by the vertebrate host is a central feature of nutritional immunity. Iron is a biologically important transition metal that plays essential roles in respiration, energy metabolism and other cellular processes using oxidation-reduction, electron transfer, and oxygen activation reactions. We speculate that tetradentate Fe III complexes formed by mono- and bis-catechol species are important Fe sources in Gram-positive human pathogens, since PiuA functions in the same way as SstD from Staphylococcus aureus. Structural analysis of PiuA Fe III- bis-catechol and Ga III- bis-catechol and Ga III-(NE) 2 complexes by NMR spectroscopy reveals only localized structural perturbations in PiuA upon ligand binding, largely consistent with recent descriptions of other solute binding proteins of type II ABC transporters. Our in vitro studies using NMR spectroscopy and 54Fe LC-ICP-MS confirm the Fe III can move from transferrin to apo-PiuA in a NE-dependent manner. Two protein-derived ligands (H238, Y300) create a coordinately-saturated Fe III complex, which parallel recent studies in the Gram-negative intestinal pathogen Campylobacter jejuni. Here we show that the solute binding lipoprotein PiuA from the piu Fe acquisition ABC transporter PiuBCDA, previously described as an Fe-hemin binding protein, binds tetradentate catechol Fe III complexes, including NE and the hydrolysis products of enterobactin. Recent studies suggest that the human catecholamine stress hormone, norepinephrine (NE), facilitates Fe acquisition in Spn under conditions of transferrin-mediated Fe starvation. Fe acquisition is a crucial virulence determinant in Spn further, Spn relies on exogenous Fe III-siderophore scavenging to meet nutritional Fe needs. Streptococcus pneumoniae (Spn) is an important Gram-positive human pathogen that causes millions of infections worldwide with an increasing occurrence of antibiotic resistance.