Hyaluronan synthase

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Hyaluronan synthase
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Hyaluronan synthases (HAS) are membrane-bound

extracellular
space.

Isoforms

There are three mammalian hyaluronan synthases described to date -

cytokines, extracellular matrix
proximities), the HAS isoforms respond differently and appear to be under different control mechanisms.

During the development of the embryo, each isoform is uniquely expressed, both spatially and temporally.

The isoforms of HAS also display varying physiological effects and therapeutic potentials. HAS2 is overexpressed in breast cancer cell lines and is associated with lymph node metastasis, while HAS1 and HAS3 lack any correlations with cancer development or metastasis.[8] HAS-2 has also been proposed as a nanotherapeutic agent to combat osteoarthritis in joints displaying synovial inflammation as a result of increased hyaluronan depolymerization.[9] Contrastingly, stimulation of HAS3 has been linked to increased inflammation and atheroprogression by means of increased interleukin release and macrophage activation.[10]

Structure

HAS1 has a single

glycosyltransferases.[13]

HAS2 is regulated by

heterodimers with each other.[14] Chlorella virus HAS (Cv-HAS) share roughly 45% sequence similarity to human HAS2.[11][13]

HAS3 is regulated through truncation of the

disulfide bonds yield a significant effect on the activity of the HAS enzymes. Hydropathy plots among the three isoforms HAS1, HAS2, and HAS3 suggest that each protein is organized in a similar manner in the membrane.[17]

Mechanism

Initiation of hyaluronan biosynthesis by Class I hyaluronan synthases involves in situ generation of an

N-acetylglucosamine (GlcNAc) primer through hydrolysis of UDP-GlcNAc, followed by diffusion of the primer into the active site.[11] The active site contains two distinct domains, each of which are capable of binding either the nascent UDP-hyaluronan chain or a UDP-sugar monomer.[18] Chain elongation, beginning from the GlcNAc primer, occurs with sequential addition of alternating UDP-GlcA and UDP-GlcNAc units to the reducing end of the growing chain.[19]

Diagram of the mechanism of hyaluronan synthase.

In each iteration of chain elongation, one active site domain is occupied by the existing UDP-hyaluronan chain. A UDP-sugar monomer corresponding to the next unit then binds to the unoccupied active site domain.

anomeric carbon of the reducing end monomer of the UDP-hyaluronan chain, displacing UDP from the hyaluronan chain and shifting the elongated chain to the domain previously occupied by the UDP-sugar monomer. Following this process, the displaced UDP dissociates from the other active site domain.[17] The process of monomer binding and elongation then repeats, with alternating GlcA and GlcNAc units being added as the UDP-hyaluronan chain shifts from one active site domain to the other.[21]

HAS1, HAS2, and HAS3 perform functionally equivalent hyaluronan biosyntheses but demonstrate differences in

epigenetic modifications.[23][24]

Role in cancer metastasis

HAS can play roles in all of the stages of cancer metastasis. By producing anti-adhesive HA, HAS can allow tumor cells to release from the primary tumor mass and if HA associates with receptors such as CD44, the activation of Rho GTPases can promote

EMT of the cancer cells. During the processes of intravasation or extravasation, the interaction of HAS produced HA with receptors such as CD44 or RHAMM promote the cell changes that allow for the cancer cells to infiltrate the vascular or lymphatic systems. While traveling in these systems, HA produced by HAS protects the cancer cell from physical damage. Finally, in the formation of a metastatic lesion, HAS produces HA to allow the cancer cell to interact with native cells at the secondary site and to produce a tumor for itself.[25]

Increased HA production by cancer cells increases invasive capacity. HA's interaction with CD44 activates focal adhesion kinase (FAK), an important molecule in the process of cell motility by coordinating dissolution of the focal adhesions at the leading edge of the cell and formation at the lagging edge.[26] Another signaling pathway activated by HA's interaction with CD44 is the Akt pathway which leads to expression of osteopontin, a molecule which can stimulate cell migration.[27] The HA produced by HAS also has been suggested to protect the cancer cell from physical damage while in the circulatory or lymphatic systems. This role of HA has been shown in other cell types, but has not yet been researched in cancer cells.[28] The HA produced by HAS up-regulates secretion of various MMPs, proteolytic enzymes that are involved in many stages of the metastatic cascade.[29] Research has shown that the different HASs may impact the metastatic steps in different ways based on the molecular weight and amount of HA they produce.

References

  1. PMID 35355017
    .
  2. PMID 9169154
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  3. PMID 12512858
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  4. PMID 10455188
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  5. PMID 16822580
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  6. PMID 10930438
    .
  7. PMID 15790861
    .
  8. PMID 26722395
    .
  9. S2CID 202745517
    .
  10. PMID 28987865
    .
  11. ^
    PMID 35355017
    .
  12. PMID 12799342
    .
  13. ^
    PMID 10988250
    .
  14. PMID 20507985
    .
  15. PMID 35671866
    .
  16. PMID 9083017
    .
  17. ^
    PMID 9206724
    .
  18. PMID 22343360
    .
  19. S2CID 21344879
    .
  20. PMID 6870820
    .
  21. S2CID 25537143
    .
  22. PMID 10455188
    .
  23. PMID 32623953
    .
  24. S2CID 53217005
    .
  25. PMID 19218337
    .
  26. PMID 12297287
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  27. PMID 19262113
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  28. S2CID 11765495
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  29. PMID 19231585
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External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Hyaluronan_synthase&oldid=1198289914"