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The "Polyphosphate Operon"
Polyphosphate metabolism is most directly controlled by several genes. Where these genes are located in their relationship to each other may be different for different organisms. Relatively well-studied organisms include members of the Pseudomonas genus as well as E.coli. Pseudomonas has been generally found to be a polyphosphate accumulator (PAO/PAB). However, it is worth noting that E.coli in particular is not know to naturally hyperaccumulate polyphosphate, leading to the complication that polyphosphate metabolism and genetic organization related to polyphosphate metabolism may be significantly different for hyperaccumulators.

Polyphosphate is synthesized by polyphosphate kinase (ppk 1 and 2). Polyphosphate is broken down by exopolyphosphatase (ppx). According to Munevar et al, neither gene are actually part of the PHO regulon (the genetic response system to inorganic P starvation).

E.coli
* insert PhoU pic here*

The PHO regulon, controlled by transcriptional regulators phoB/phoR in this case, regulates the pstSCAB genes, which together encode for a high-affinity phosphate transporter; the regulon also regulates pit, a low-affinity P transporter. The remaining gene in the PHO regulon is phoU, which is thought to regulate the expression of this operon, as well as genes not part of the PHO regulon such as ppx and ppk (see Pseudomonas section). It is not known exactly how it performs.

The regulon is normally shut off (by pstSCAB and phoU proteins) when P is in excess. In the case of PhoU mutation (inactivating), polyP was found to accumulate to abnormally "high levels". It is theorized that polyP accumulation is limited in wild-type E.coli by P intake, not polyP production or other reasons. Based on this, and the observation that with PhoU inactivated there was an observed increase in P intake regardless of high surrounding P content in the media, it is suggested that PhoU knockout mutations result in constitutive expression of the high-affinity P transporter pstSCAB genes.

This operon structure is similar in Pseudomonas aeruginosa, with minor differences in where the PHO-boxes are located within the operon.

Pseudomonas
By generating a null phoU mutant, which results in no transcription or translation of phoU protein, polyphosphate accumulation increases significantly along with increased ppk expression, decreased ppx expression, and increased ppGpp concentration within the cell. Polyphosphate accumulation of phoU mutant increased 19X the wt average.

Post-transcriptional Interactions
(P)ppGpp is a well-studied stress-related signal molecule. Intracellular abundance tends to be associated with starvation conditions in the case polyP accumulation. (P)ppGpp accumulates to high levels upon phoU knockout in Pseudomonas. While this is not necessarily responsible for hyperaccumulating phenotypes, ppGpp does "interact with the exopolyphosphatase PPX, inhibiting its activity." This may be important for manipulation of ppx in future experiments.

PolyP itself is also a signaling molecule known to inhibit or activate various enzymes.

In E.Coli, PhoU interacts with PhoR (regulatory protein), PstB (part of the PstSCAB high-affinity P transporter), manganese and/or magnesium. Magnesium and manganese sometimes act as stand-ins for each other in enzymatic processes that involve one or the other, and magnesium typically higher in intracellular abundance. In other organisms, PhoU bins iron clusters or zinc. According to Gardner et al, this metal binding may be critical to PhoU function. The metal-binding regions of PhoU are reportedly highly conserved.