Metabolism

Metabolic Significance of Serine

The enzyme serine palmitoyltransferase (SPT) catalyzes the condensation of serine and palmitoyl CoA, the first step in the formation of sphingolipids. SPT activity is a key regulatory factor in this biosynthetic pathway, as it can prevent overaccumulation of harmful sphingolipid-intermediates (such as sphingoid bases or ceramide) when downstream processes are repressed.⁸ Conversely, overexpression of SPT can result in the formation of excess sphingolipids. Sphingolipids regulate cell growth by serving as a secondary messenger in signaling cascades. Therefore, excess amounts of sphingolipids present can result in uncontrolled cell growth – cancer. One solution to prevent cancerous growth is to limit the amount of serine available for SPT to interact with. With low levels of serine, however, the individual will begin to experience loss of vision. Thus, the optimal level of serine must be studied in order to limit cancer growth while preserving the health of the individual. In addition, certain cell types and tissues lack the ability to synthesize or take up some NEAAs therefore dietary influence is important."

Mutations and Errors

Genetic disorders arising from missense mutations have adverse effects on the sphingolipid biosynthesis pathway. Hereditary sensory and autonomic neuropathy type 1 (HSAN 1) arises from the mutation C133W, which alters the active site of SPT. In turn, the specificity of SPT is reduced and SPT begins catalyzing the condensation reaction of alanine (or glycine) with palmitoyl CoA.1 1 The new products of this reaction are deoxysphingoid bases, which cannot be further used to synthesize sphingolipids. Accumulation of these deoxysphingoid bases typically results in sensory loss, specifically the inability to feel temperature. Furthermore, atypical deoxysphingolipids can be formed from the deoxysphingoid bases, which can also lead to vision loss. While wild-type SPT exhibits fairly high specificity, mutations can disrupt its function and create complications for the individual.

Conclusion

A biologically and mechanically stable design for cell culture and tissue organization is important in medicine and tissue engineering. Delivery of constant nutrients and metabolites is important in maintenance of consistent environmental conditions. Perfusion bioreactors are ideal due to cost efficiency, simplicity of use, and scalability. Bioreactors have been used successfully to cultivate cells, in addition to 3D scaffolds for tissue organization. We intend to design a bioreactor for culture of cancerous cells where NEAA pathways, particularly serine, are affected resulting in dysregulation of cell growth. Combining the functions of maintaining biological culturing conditions and detection of cellular NEAA levels, we may develop a perfusion bioreactor ideal for experimentation with cancer cells. This would greatly simplify cancer cell culture and similar immunology studies.

References

Gantner, Marin L., et al. “Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy.” New England Journal of Medicine, Sept. 2019. world, www.nejm.org, doi:10.1056/NEJMoa1815111.

“Neuropathy Presentation | El Paso, TX. | Doctor Of Chiropractic.” El Paso, TX Doctor Of Chiropractic, 22 May 2018, https://www.dralexjimenez.com/neuropathy-presentation-el-paso-tx-part-i/.