Undecaprenyl phosphate (UP), also known lipid-P, bactoprenol and C55-P., is a molecule with the primary function of trafficking

polysaccharide Polysaccharides (), or polycarbohydrates, are the most abundant carbohydrates found in food. They are long-chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. This carbohydrate can react with wat ...

s across the cell membrane, largely contributing to the overall structure of the cell wall in

Gram-positive bacteria In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. The Gram stain ...

. In some situations, UP can also be utilized to carry other cell-wall polysaccharides, but UP is the designated

lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...

carrier for peptidoglycan. During the process of carrying the peptidoglycan across the cell membrane, ''N''-acetylglucosamine and ''N''-acetylmuramic acid are linked to UP on the cytoplasmic side of the membrane before being carried across. UP works in a cycle of

phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

and

dephosphorylation In biochemistry, dephosphorylation is the removal of a phosphate () group from an organic compound by hydrolysis. It is a reversible post-translational modification. Dephosphorylation and its counterpart, phosphorylation, activate and deactivate e ...

as the lipid carrier gets used, recycled, and reacts with undecaprenyl phosphate. This type of synthesis is referred to as ''de novo'' synthesis where a complex molecule is created from simpler molecules as opposed to a complete recycle of the entire structure. The synthesis of UP differs between

Gram-negative Gram-negative bacteria are bacteria that, unlike gram-positive bacteria, do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. Their defining characteristic is that their cell envelope consists ...

and Gram-positive bacteria. In Gram-positive bacteria, undecaprenol is found in vast quantities, which is then phosphorylated into UP. For Gram-negative bacteria however, there has yet to be any indication that they contain any undecaprenol at all. Instead of having an undecaprenol be phosphorylated, it appears that instead, Gram-negative bacteria undergo a dephosphorylation of undecaprenyl diphosphate which is catalyzed by both a type-2 phosphatidic acid, phosphatase homologue, and a BacA homologue. Undecaprenyl phosphate is also known to be the "Universal Glycan Lipid Carrier". When UP is inhibited, the

peptidoglycan Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like layer (sacculus) that surrounds the bacterial cytoplasmic membrane. The sugar component consists of alternating ...

synthesis is interrupted and it could lead to cell lysis. Furthermore, UP is involved in the metabolism of many cellular processes that can potentially be targeted by antibiotics. Also, it is common for bacteria to use UP to translocate

glycan The terms glycans and polysaccharides are defined by IUPAC as synonyms meaning "compounds consisting of a large number of monosaccharides linked glycosidically". However, in practice the term glycan may also be used to refer to the carbohydrate ...

; however, certain bacteria do not use undecaprenyl phosphate as a glycan translocator.

Biosynthetic processes

Peptidoglycan synthesis

UP is involved in transporting

subunits from the cytoplasmic face of the cell membrane to the

periplasm The periplasm is a concentrated gel-like matrix in the space between the inner cytoplasmic membrane and the bacterial outer membrane called the ''periplasmic space'' in Gram-negative (more accurately "diderm") bacteria. Using cryo-electron micros ...

ic or extracellular surface. In the process, UP (also called lipid-P) complexes with UDP-''N''-acetylmuramic acid pentapeptide (UDP-NAM pentapeptide) to form lipid I, displacing UMP. From there, lipid I complexes with ''N''-acetyl glucosamine (NAG) to form lipid II. Lipid II then is flipped across the membrane by a flippase to the outside leaflet of the cell membrane. The NAG-NAM pentapeptide subunit is then added onto the growing peptidoglycan chain, leaving behind undecaprenyl diphosphate. The extra phosphate on undecaprenyl diphosphate is cleaved by a pyrophosphatase and UP is then recycled to the cytoplasmic face of the cell membrane.

O-antigen synthesis in lipopolysaccharide assembly

UP also serves as the lipid transporter for the O-antigen component of lipopolysaccharide. It is supposed that sugars are assembled into O-antigen subunits directly on UP on the cytoplasmic surface of the cell membrane. Then the UP-O-antigen subunit gets flipped to the other side of the membrane, where similar UP-O-antigen subunits interact and aggregate the O-antigen subunits into repeating-subunit chains, leaving undecaprenyl diphosphate behind. Again undecaprenyl phosphate is recycled by a pyrophosphatase and flipped to the cytoplasmic face again.

Inhibition

UP is a valuable transporter for cell wall equipment. That being said, the components necessary for the proper UP functioning can be inhibited, restricting the aiding of cell wall synthesis. As a result, the bacteria's structure is compromised, and its ability to combat lysing is lost. On a larger scale, this is helpful when fighting, or preventing bacterial infections.

Bacitracin Bacitracin is a polypeptide antibiotic. It is a mixture of related cyclic peptides produced by '' Bacillus licheniformis'' bacteria, that was first isolated from the variety "Tracy I" ( ATCC 10716) in 1945. These peptides disrupt Gram-positiv ...

is an example of one of these antibiotics. It is a generic topical cream used for "cuts, scrapes, and burns", possessing "bacteriostatic and bactericidal properties". The process is accomplished by targeting and inhibiting the enzyme used to renew UP—membrane-bound undecaprenyl phosphatase hydrolyzing undecaprenyl diphosphate to UP. This renewal process is crucial for maintaining the flow of lipid I and lipid II across the membrane, and without it, the cell wall synthesis process is halted.

Clomifene Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. It is taken by mouth. Common side effects include pelvic pain and hot flashes. Oth ...

, a medication used to treat infertility in women, is another UP inhibitor discovered in the last decade. It has a similar process of cell wall disruption as bacitracin, resulting with lysis of cells. While Bacitracin and clomiphene are not the only inhibitors out there, they are two on the evolving list that have been experimentally proven to inhibit pyrophosphatase.

References

{{reflist Phosphates