POLYAMINES synthesis, catabolism and functions
- 2. Introduction Biosynthesis of Polyamines Degradation of Polyamines Functions of Polyamines Clinical importance
- 3. Polyamines are the aliphatic amines possessing multiple amino groups. Polyamines are originally identified in sperms, but now they are known to exist in number of other tissues. Biologically important polyamines are PUTRESCINE, SPERMIDINE, SPERMINE.
- 4. PUTRESCINE - 1,4 diamino butane (or) 1,4 butane diamine. (CH2)4 (NH2)2. SPERMIDINE- 4 aza octa methyl enediamine (or) 1,5,10 tri aza decane. C7H19N3. SPERMINE- poly azaalkane 1,5,10,14 carbon positions are replaced by nitrogens. C10 H26N4.
- 5. BIOSYNTHESIS OF POLYAMINES Arginine and S adenosyl Methionine (SAM) acts as the precursors for polyamines. Arginine by the action of enzyme ARGINASE gives ORNITHINE. Ornithine decarboxylase – is a PLP dependent enzyme catalyses the decarboxylation of ornithine to form PUTRESCINE.
- 6. Ornithine decarboxylase is induced by steroid hormones. ODC gene is present on the chromosome 2. Has the shortest half life ( about 5min). S- adenosyl methionine decarboxylase- responsible for the formation of Spermidine. Firstly on Adenylation, Methionine gets converted into its active form S-adenosyl Methionine (SAM), catalyzed by the enzyme Methionine adenosyl transferase.
- 7. SAM-decarboxylase catalyses the decarboxylation of SAM to Decarboxy- SAM (DSAM). Later DSAM converts to methyl thioadenosine by liberating amino propane. Amino propane donates amino group to Putrescine to form SPERMIDINE and the reaction is catalyzed by Spermidine synthase.
- 8. Later another amino group is donated by amino propane to Spermidine to form SPERMINE and the reaction is catalyzed by Spermine synthase enzyme. SAM-decarboxylase enzyme is present on the chromosome 6 & X.
- 10. DEGRADATION OF POLYAMINES Catabolism of polyamines is essential for maintaining polyamine ratio associated with intracellular polyamine homeostasis. Polyamines are degraded in the liver cells by Polyamine oxidase. It converts Spermine to Spermidine and then to Putrescine. Putrescine is oxidized to carbondioxide and ammonia.
- 13. Transport of polyamines transported via specific plasma membrane transport based on cell requirements called as Polyamine Transport Systems. This mechanism hasnot been fully elucidated yet in mammalian cells. Presently advocated PTS are : Glypican mediated endocytosis. Caveolin mediated endocytosis. PTS also might be an entry gate target of cytotoxic polyamine conjugated drugs.
- 14. Functions Polyamines are basic in nature having multiple positive charges . So they readily associate with negatively charged cellular macromolecules such as nucleic acids. They also interact with membrane phospholipids and negatively charged residues of membrane bound proteins. Required for protein biosynthesis.
- 15. The translation intiation factor eIF- 4D contains Hypusine residue. Hypusine is formed by addition of butylamine moiety from spermidine to Lysine. IF-4D is the only known protein containing Hypusine. They take part in chromatin remodeling, gene transcription and translation. They have the role in hormone mediated actions and in membrane fusion during exocytosis and endocytosis.
- 16. Clinical importance As they play role in cell proliferation, synthesis of DNA &RNA, protection of DNA against depurination – polyamine concentration increases in cancer tissues. They are excreted in large concentrations in several types of malignancies suchas Cancers of Lung, Kidney, Urinary Blader, Prostate, Skin and Colon. Polyamines are classified under Miscellanous tumor markers.
- 17. High levels of polyamines have been linked to more immunosuppressive tumor microenvironments as polyamines support growth and function of many immunosuppressive cell types suchas MDSCs, macrophages and regulatory Tcells. Polyamines also inhibit lymphocyte proliferation, IL-2 production, macrophage mediated tumoricidal activity, neutrophil locomotion, IL-2 dependent NK cells activity invitro.
- 18. High polyamine levels seen in Neuroblastoma Hepato cellular carcinoma Prostate cancer Carcinoma lung Carcinoma Breast Gastric cancer Colorectal cancer. Low polyamine levels leads to apoptosis of post mitotic and senescent cells.
- 20. Ornithine decarboxylase (ODC) is directly controlled by MYC gene. Upregulation or amplification of MYC gene leads to increased polyamine biosynthesis in malignant tumors. Once SAM has been decarboxylated to serve as the aminopropyl donor in polyamine biosynthesis, it is no longer available to be used as a methyl donor in transmethylation reactions.
- 21. Elevated decarboxylated SAM levels result in decreased activity of DNA methyltransferases and can result in dysregulated global methylation status and global transcriptional changes. As such, polyamines are implicated in the Epigenetic regulation of both Ageing and Cancer development and survival.
- 22. Di fluoro methyl ornithine (DFMO) is a powerful inhibitor of Polyamine synthesis. It is an example of irreversible suicide inhibition. DFMO is inhibitor of ornithine decarboxylase and it acts as Anticancer drug. DFMO also used in the treatment of KAALA- AZAR and African sleeping sickness. Also acts against pneumocystis carinii infection which is common in AIDS.
- 23. Tumor suppressor gene P53 – most common mutated gene in human tumors. is a negative cellcycle regulator Acts on G1check point. P53 activates spermidine acyl transferase 1 (SAT 1) which causes Lipid peroxidation Ferroptosis Repress the urea cycle Induce Ammonia metabolism leading to Ammonia accumulation and decreases ODC levels and cell proliferation.
- 24. ODC inhibition by DFMO is also caused by p53 induction. fragile site associated tumor suppressor (FATS) activated by p53 in response to DNA damage. FATS binds to estrogen receptor translocatees to cytosol, inhibits ODC at protein and mRNA levels. Polyamines play important role in maintenance of immune privilege.
- 25. Polyamine inhibition has benefits suchas the potential to be used as adjuvant cancer therapy. The ability to be combined with conventional chemotheraupetic agents and the ability to stimulate responses to tumor immunotherapies.
- 26. References Vasudevan Harper Dineshpuri Pubmed journal.