Role of Polyamines in Prolactin Actions
James A. Rillema in Actions of Prolactin on Molecular Processes, 1987
Polyamine biosynthesis in eukaryotic cells involves several precursors such as arginine, ornithine, methionine, and S-adenosylmethionine (Figure 2). Ornithine is mainly formed in the urea cycle through the cleavage of urea from arginine by arginase. Ornithine is then converted to putrescine in a reaction catalyzed by ornithine decarboxylase (ODC).29–31S-Adenosylmethionine is a universal methyl donor in transmethylation reactions. In polyamine biosynthesis, this compound is first decarboxylated by S-adenosylmethionine decarboxylase (S-ado-met DC).29–31S-Ado-met serves as the propylamine donor in the formation of spermidine from putrescine by spermidine synthase as well as in the formation of spermine from spermidine by spermine synthase.29–31
Eflornithine
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
Eflornithine is an enzyme-activated irreversible inhibitor of the enzyme ornithine decarboxylase (ODC), one of the key enzymes in the polyamine biosynthetic pathway (Kaminsky and Mäser, 2000). Ornithine decarboxylase converts ornithine to putrescine, the first step in the synthesis of the cellular proteins spermidine and spermine (Bacchi et al., 1980; Harder et al., 2001). These proteins are essential for growth, as they affect nucleic acid synthesis and contribute to the regulation of protein synthesis, including conformational stabilizers for nucleic acids (McCann and Pegg, 1992; Pepin and Milord, 1994; Bacchi and Yarlett, 2002). As an ornithine analog, eflornithine acts as a suicide inhibitor, binding covalently to ODC and completely inactivating this enzyme (McCann and Pegg, 1992). The depletion of putrescine and spermidine leads to the arrest of proliferation (Bacchi et al., 1983; Wallace and Fraser, 2004). In a rodent model the mechanism of action of eflornithine was determined to be via an active metabolite that inhibited ODC by alkylating a nucleophilic residue (Pegg et al., 1987). This molecule bound irreversibly to the enzyme, in keeping with the functional inactivation observed.
Pneumocystis carinii
Peter D. Walzer, Robert M. Genta in Parasitic Infections in the Compromised Host, 2020
There is accumulating evidence that DFMO represents a new type of therapeutic approach to P. carinii pneumonia (147,473,474). This drug inhibits ornithine decarboxylase, a necessary step in the synthesis of polyamines, which play an important role in the replication of eukaryotic cells. While DFMO has inhibitory effects on a variety of protozoans, its main clinical use has been in the treatment of African trypanosomiasis. The use of DFMO in the treatment of P. carinii pneumonia has mainly been on a compassionate basis in patients who have failed or have experienced serious adverse reactions to TMP-SMX or pentamidine. The clinical experience with DFMO in more than 100 patients with pneumocystosis has been briefly summarized in a recent symposium (147). Of 53 persons who received the drug for more than 2 weeks, 70% achieved a good clinical response; 12 of these responders had begun therapy on ventilator support. DFMO was usually well tolerated, with adverse reactions (e.g., thrombocytopenia, leukopenia, high-frequency hearing loss, patchy alopecia, diarhhea) being reversible upon reduction in dose or cessation of therapy.
Evolving treatments in high-risk neuroblastoma
Published in Expert Opinion on Orphan Drugs, 2020
Abhinav Kumar, John P J Rocke, B Nirmal Kumar
MYCN amplification has become synonymous with high-risk neuroblastoma formation but was often considered undruggable. Therefore, newer approaches are looking to target regulators of MYCN transcription. Ornithine Decarboxylase (ODC) is an enzyme involved in the biosynthesis of polyamines that supports N-MYC proteins, with the inhibition of this downstream regulator possibly slowing the growth of neuroblastomas [63]. Difluoromethylornithine (DFMO) is an irreversible inhibitor of ODC and has shown to have low toxicity in humans, with certified medical use for conditions such as trypanosomiasis [64]. Whilst DMFO targeting ODC is a possible treatment for MYCN-amplified neuroblastomas, elevated ODC is also seen in non-MYCN amplified neuroblastomas indicating that increased ODC expression is critical in all rapidly dividing tumor cells [65]. In an pre-clinical study of DMFO efficacy, the drug not only inhibited tumor growth in MYCN-amplified mice leading to prolonged survival, but also showed efficacy as an adjuvant to conventional chemotherapy [66]. In a phase 1 trial, DMFO showed no significant toxicities with or without etoposide (a chemotherapeutic agent) in patients with relapsed neuroblastoma [67]. Additionally, this study further emphasized the importance of ODC as an indicator of poor prognosis in neuroblastoma patients. A phase 2 trial is underway to assess oral DMFO as a maintenance therapy in high-risk cases [NCT02395666]. Whilst relatively un-tested for neuroblastoma, a well-tolerated and widely applicable drug such as DMFO could be very useful.
Polyamine biomarkers as indicators of human disease
Published in Biomarkers, 2021
Mohsin Amin, Shiying Tang, Liliana Shalamanova, Rebecca L. Taylor, Stephen Wylie, Badr M. Abdullah, Kathryn A. Whitehead
The use of polyamines in the detection of cancer has been studied throughout the literature since it has been suggested that their role in the pathogenesis of cancers such as prostate, colon and pancreatic, is apparent (Soda 2011, Nowotarski et al.2013, Damiani and Wallace 2018). The first reported role of polyamines in cancer was documented by Russell and Snyder (1968), whereby the increased levels of ornithine decarboxylase (ODC), a biosynthetic polyamine enzyme, was identified in various pathological cancers, such as liver and breast cancer (Russell and Snyder 1968, Deng et al.2008). When suppressed, the activity of ODC, the rate-limiting enzyme for mammalian polyamine biosynthesis, showed inhibition of colon carcinogenesis in cancer rodent models. Such a finding may suggest that the reduction in polyamine biosynthesis demonstrated a positive correlation in reducing the rates of colon cancer in rodents (Erdman et al.1999).
Effects of a synbiotic on the fecal microbiome and metabolomic profiles of healthy research cats administered clindamycin: a randomized, controlled trial
Published in Gut Microbes, 2019
Jacqueline C. Whittemore, Jennifer E. Stokes, Joshua M. Price, Jan S. Suchodolski
In this study, marked reductions in relative abundance of Bacteroides spp and members of the Clostridium subcluster XIVa occurred, and abundances for Ruminococcaceae spp significantly differed between treatment groups. Profiles for squalene and putrescine differed significantly over time, with concurrent significant differences between treatment groups for squalene. Similar changes were found in the previously mentioned studies of the microbiome1,3 and metabolome1 of cats administered antibiotics with or without pro- or synbiotics. In the latter study, putrescine profiles were persistently reduced in cats administered clindamycin with a placebo while similar suppression was not identified in cats administered a synbiotic. Squalene previously has been found to inhibit ornithine decarboxylase,36 which is responsible for conversion of ornithine to putrescine, the first of several polyamines. Because squalene is an intermediate in the biosynthesis of cholesterol,36 alterations in its profiles also must be considered in concert with noted changes for dihydrocholesterol profiles. As such, concomitant quantification of bacterial changes and polyamine concentrations in the mucosa and feces of animals administered antibiotics with and without synbiotics will be necessary to determine whether ameliorative effects of synbiotics on AAGS are mediated through maintenance of polyamine concentrations.
Related Knowledge Centers
- Cofactor
- Lysine
- Ornithine
- Polyamine
- Protein Dimer
- Putrescine
- Pyridoxal Phosphate
- Urea Cycle
- Amino Acid
- Committed Step