Yersiniabactin is a siderophore

Siderophore

Siderophores are small, high-affinity iron chelating compounds secreted by grasses and microorganisms such as bacteria and fungi...

 found in the pathogenic bacteria

Bacteria

Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

 Yersinia pestis, Yersinia pseudotuberculosis, and Yersinia enterocolitica, as well as several strains of enteropathogenic Escherichia coli. Siderophores, compounds of low molecular mass with high affinities for ferric iron, are important virulence factors in pathogenic bacteria. Iron, an essential element for life utilized by such cellular processes as respiration

Cellular respiration

Cellular respiration is the set of the metabolic reactions and processes that take place in the cells of organisms to convert biochemical energy from nutrients into adenosine triphosphate , and then release waste products. The reactions involved in respiration are catabolic reactions that involve...

 and DNA replication, is extensively chelated by host proteins like lactoferrin

Lactoferrin

Lactoferrin , also known as lactotransferrin , is a multifunctional protein of the transferrin family. Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa that is widely represented in various secretory fluids, such as milk, saliva, tears, and nasal secretions...

 and ferritin

Ferritin

Ferritin is a ubiquitous intracellular protein that stores iron and releases it in a controlled fashion. The amount of ferritin stored reflects the amount of iron stored. The protein is produced by almost all living organisms, including bacteria, algae and higher plants, and animals...

; thus, the pathogen produces molecules with an even higher affinity for Fe3+ than these proteins in order to acquire sufficient iron for growth. As a part of such an iron-uptake system, yersiniabactin plays an important role in pathogenicity of Y. pestis, Y. pseudotuberculosis, and Y. entercolitica.

Structure and coordination properties

Yersiniabactin is a four ring structure composed of carbon, hydrogen, nitrogen, oxygen, and sulfur. According to X-ray crystallography

X-ray crystallography

X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread into many specific directions. From the angles and intensities of these diffracted beams, a crystallographer can produce a...

, it binds Fe³⁺as a 1:1 complex by three nitrogen electron pairs and three negatively charged oxygen atoms with a distorted octahedral structure. The Ybt-Fe³⁺ complex has a proton-independent formation constant of 4 x 10³⁶.

Biosynthesis

Ybt synthesis occurs by a mixed nonribosomal peptide synthetase (NRPS)/polyketide synthase

Polyketide synthase

Polyketide synthases are a family of multi-domain enzymes or enzyme complexes that produce polyketides, a large class of secondary metabolites, in bacteria, fungi, plants, and a few animal lineages...

 (PKS) mechanism. Several enzymes, most notably the HMWP2-HMWP1complex, assemble salicylate, three cysteines, a malonyl linker group and three methyl groups into a four-ring structure made of salicylate, one thiazolidine, and two thiazoline rings with a malonyl linker between the thiazoline and the thiazolidine. YbtD, a phosphopantetheinyl transferase, adds phosphopantetheine tethers to the cysteine, salicylate and malonyl groups to HMWP1 and HMWP2. YbtS synthesizes salicylate from chorismate, which is then adenylated by YbtE and transferred to the HMWP2–HMWP1 assembly complex. HMWP2, which consists of two multidomain NRPS modules, accepts the activated salicylate unit through a carrier protein, then cyclizes and condenses two cysteines to form two thiazoline

Thiazoline

Thiazoline is a heterocyclic compound containing both sulfur and nitrogen in the ring. Although thiazoline itself is rarely encountered, its derivatives are often bioactive. For example, in a common post-translational modification, cysteine residues are converted into...

 rings. A malonyl linker is added by the PKS portion of HMWP1, and YbtU reduces the second thiazoline ring to thiazolidine

Thiazolidine

Thiazolidines are a class of heterocyclic organic compounds with a 5-membered saturated ring with a thioether group and an amine group in the 1 and 3 positions, respectively. It is a sulfur analogue of oxazolidine. The drug pioglitazone contains a thiazolidine ring. It is a drug usually indicated...

before cyclization and condensation of the final thiazoline ring on HMWP1’s NRPs domain. YbtT thioesterase may serve some editing function to remove abnormal molecules from the enzyme complex, and a thioesterase domain of HMWP1 releases the completed siderophore from the enzyme complex.

Regulation of expression

The HPI upon which the genes encoding the Ybt biosynthesis proteins are located is controlled by a series of molecular regulators. All four promoter regions of the yersiniabactin region (psn, irp2, ybtA and ybtP) possess a Fur-binding site and are negatively regulated by this repressor in the presence of iron. In the presence of Ybt, a member of the AraC family of transcriptional regulators, activates expression from the psn, irp2 and ybtP (transport and biosynthetic genes) promoters but represses expression of its own promoter. There is also evidence that yersiniabactin itself may upregulate its own expression and that of psn/fyuA and ybtPQXS at the transcription level.

Role in Yersinia pathogenicity

As previously mentioned, siderophores serve the essential function of iron acquisition for pathogens in the low iron conditions of the host. Thus the successful establishment of disease depends on the ability of the invading organism to acquire iron. Because of its high affinity for iron, yersiniabactin can solubilize the metal bound to host binding proteins and transport it back to the bacteria. The complex yersiniabactin-Fe3+ recognizes the specific bacterial outer membrane receptor TonB and is translocated with the help of membrane-embedded proteins into the cytosol where the iron is discharged from yersiniabactin and utilized in various metabolic pathways. In the absence of a high-affinity iron-chelating compound, pathogenic Yersinia, responsible for such lethal disease as the bubonic plague, only causes local symptoms of moderate intensity. The availability of iron, through an intrinsic high-affinity iron-chelating system such as Ybt, provides the bacteria with the ability to multiply in the host and to cause systemic infections.