bims-polyam 2021-01-17 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2021–01–17
eight papers selected by
Sebastian J. Hofer, University of Graz

Polyamine Biomarkers as Indicators of Human Disease.
Rice yellow stunt virus activates polyamine biosynthesis to promote viral propagation in insect vectors by disrupting ornithine decarboxylase antienzyme function.
Regulation of polyamine homeostasis through an antizyme citrullination pathway.
Updates on the molecular mechanisms of aspirin in the prevention of colorectal cancer: Review.
X-ray Crystallographic Snapshots of Substrate Binding in the Active Site of Histone Deacetylase 10.
Exploiting Spermidine N-Hydroxycinnamoyltransferase Diversity and Substrate Promiscuity to Produce Various Trihydroxycinnamoyl Spermidines and Analogues in Engineered Yeast.
Plasma metabolites associated with chronic kidney disease and renal function in adults from the Baltimore Longitudinal Study of Aging.
Adipocyte-specific GPRC6A ablation promotes diet-induced obesity by inhibiting lipolysis.

Biomarkers. 2021 Jan 13. 1-75

Polyamine Biomarkers as Indicators of Human Disease.

Mohsin Amin, Shiying Tang, Liliana Shalamanova, Rebecca L Taylor, Stephen Wylie, Badr M Abdullah, Kathryn A Whitehead.

  The significant increase of periodontitis, chronic kidney disease (CKD), Alzheimer's disease and cancer can be attributed to an ageing population. Each disease produces a range of biomarkers that can be indicative of disease onset and progression. Biomarkers are defined as cellular (intra/extracellular components and whole cells), biochemical (metabolites, ions and toxins) or molecular (nucleic acids, proteins and lipids) alterations which are measurable in biological media such as human tissues, cells or fluids. An interesting group of biomarkers that merit further investigation are the polyamines. The polyamines are a group of molecules consisting of cadaverine, putrescine, spermine and spermidine and these have been implicated in the development of a range of systemic disease, in part due to their production in periodontitis. Cadaverine and putrescine within the periodontal environment have demonstrated cell signalling interfering abilities, by way of leukocyte migration disruption. The polyamines spermine and spermidine in tumour cells have been shown to inhibit cellular apoptosis, effectively prolonging tumorigenesis and continuation of cancer within the host. Polyamine degradation products such as acrolein have been shown to exacerbate renal damage in CKD patients. Thus, the use of such molecules has merit to be utilised in the early indication of such diseases in patients.

Keywords:  Alzheimer’s Disease; Biomarkers; Cancer; Chronic Kidney Disease; Periodontitis; Polyamines

DOI:  https://doi.org/10.1080/1354750X.2021.1875506
Sci China Life Sci. 2021 Jan 08.

Rice yellow stunt virus activates polyamine biosynthesis to promote viral propagation in insect vectors by disrupting ornithine decarboxylase antienzyme function.

Xiao-Feng Zhang, Tianbao Zeng, Yunjie Xie, Yuemin Zheng, Huanqin Wang, Hanbin Lin, Zongwen Wang, Taiyun Wei.

  Intracellular polyamines (putrescine, spermidine, and spermine) have emerged as important molecules for viral infection; however, how viruses activate polyamines biosynthesis to promote viral infection remains unclear. Ornithine decarboxylase 1 (ODC1) and its antienzyme 1 (OAZ1) are major regulators of polyamine biosynthesis in animal cells. Here, we report that rice yellow stunt virus (RYSV), a plant rhabdovirus, could activate putrescine biosynthesis in leafhoppers to promote viral propagation by inhibiting OAZ1 expression. We observed that the reduction of putrescine biosynthesis by treatment with difluormethylornithine (DFMO), a specific nontoxic inhibitor of ODC1, or with in vitro synthesized dsRNAs targeting ODC1 mRNA could inhibit viral infection. In contrast, the supplement of putrescine or the increase of putrescine biosynthesis by treatment with dsRNAs targeting OAZ1 mRNA could facilitate viral infection. We further determined that both RYSV matrix protein M and ODC1 directly bind to the ODC-binding domain at the C-terminus of OAZ1. Thus, viral propagation in leafhoppers would decrease the ability of OAZ1 to target and mediate the degradation of ODC1, which finally activates putrescine production to benefit viral propagation. This work reveals that polyamine-metabolizing enzymes are directly exploited by a vector-borne virus to increase polyamine production, thereby facilitating viral infection in insect vectors.

Keywords:  leafhopper; plant virus; polyamines; rice yellow stunt virus; viral infection

DOI:  https://doi.org/10.1007/s11427-020-1846-8
J Cell Physiol. 2021 Jan 11.

Regulation of polyamine homeostasis through an antizyme citrullination pathway.

Yi-Fang Yang, Chien-Yun Lee, Ju-Yi Hsieh, Yi-Liang Liu, Chi-Li Lin, Guang-Yaw Liu, Hui-Chih Hung.

  This study reveals an uncovered mechanism for the regulation of polyamine homeostasis through protein arginyl citrullination of antizyme (AZ), a natural inhibitor of ornithine decarboxylase (ODC). ODC is critical for the cellular production of polyamines. AZ binds to ODC dimers and promotes the degradation of ODC via the 26S proteasome. This study demonstrates the protein citrullination of AZ catalyzed by peptidylarginine deiminase type 4 (PAD4) both in vitro and in cells. Upon PAD4 activation, the AZ protein was citrullinated and accumulated, leading to higher levels of ODC proteins in the cell. In the PAD4-overexpressing and activating cells, the levels of ODC enzyme activity and the product putrescine increased with the level of citrullinated AZ proteins and PAD4 activity. Suppressing cellular PAD4 activity reduces the cellular levels of ODC and downregulates cellular polyamines. Furthermore, citrullination of AZ in the C-terminus attenuates AZ function in the inhibition, binding, and degradation of ODC. This paper provides evidence to illustrate that PAD4-mediated AZ citrullination upregulates cellular ODC and polyamines by retarding ODC degradation, thus interfering with the homeostasis of cellular polyamines, which may be an important pathway regulating AZ functions that is relevant to cancer biology.

Keywords:  anti-citrullinated AZ antibody; antizyme; ornithine decarboxylase; peptidylarginine deiminase; polyamines; protein citrullination

DOI:  https://doi.org/10.1002/jcp.30252
J Oncol Pharm Pract. 2021 Jan 11. 1078155220984846

Updates on the molecular mechanisms of aspirin in the prevention of colorectal cancer: Review.

Yaschilal Muche Belayneh, Gedefew Getnet Amare, Birhanu Geta Meharie.

  Colorectal cancer is one of the commonest malignancies worldwide. The estimated lifetime risk of the disease is about 5% with an incidence of one million new cases and 600,000 deaths worldwide every year. It is estimated that in 2019, approximately 134,490 new cases of colorectal cancer will be diagnosed with 49,190 mortalities. Though the disease is regarded as a disorder of the more developed world, the occurrence is steadily increasing in many developing countries. Since chronic inflammation is a known aggravating risk factor for colorectal cancer, anti-inflammatory agents such as aspirin have been used to prevent the development of colorectal cancer and related mortality. The potential mechanisms for the effect of aspirin in the prevention of colorectal cancer have been proposed and broadly classified as cyclooxygenase (COX) dependent and COX-independent. Some of the primary effectors of COX-dependent mechanisms in carcinogenesis are likely to be prostaglandins. In contrast to the reversible action of other nonsteroidal anti-inflammatory drugs, aspirin is known to irreversibly inactivate COX enzymes to suppress production of prostaglandins. COX-independent mechanisms of anticancer effects of aspirin include down-regulation of nuclear factor kappa B activity and Akt activation, modulation of Bcl-2 and Bax family proteins, suppression of vascular endothelial growth factor, induction of apoptosis, disruption of DNA repair mechanisms, and induction of spermidine/spermine N1-acetyltransferase that modulates polyamine catabolism.

Keywords:  Aspirin; colorectal cancer; molecular mechanism; prevention

DOI:  https://doi.org/10.1177/1078155220984846
Biochemistry. 2021 Jan 15.

X-ray Crystallographic Snapshots of Substrate Binding in the Active Site of Histone Deacetylase 10.

Corey J Herbst-Gervasoni, David W Christianson.

Histone deacetylase 10 (HDAC10) is a zinc-dependent polyamine deacetylase enriched in the cytosol of eukaryotic cells. The active site of HDAC10 contains catalytic residues conserved in other HDAC isozymes that function as lysine deacetylases: Y307 assists the zinc ion in polarizing the substrate carbonyl for nucleophilic attack, and the H136-H137 dyad serves general base-general acid functions. As an inducer of autophagy, HDAC10 is an attractive target for the design of selective inhibitors that may be useful in cancer chemotherapy. Because detailed structural information regarding the catalytic mechanism of HDAC10 may inform new approaches to inhibitor design, we now report X-ray crystal structures of HDAC10 in which reaction intermediates with substrates N8-acetylspermidine and N-acetylputrescine are trapped in the active site. The Y307F substitution prevents activation of the substrate carbonyl for nucleophilic attack by the zinc-bound water molecule, thereby enabling crystallographic isolation of intact enzyme-substrate complexes. The H137A substitution removes the catalytically obligatory general acid, thereby enabling crystallographic isolation of oxyanionic tetrahedral intermediates. Finally, the acetate complex with the wild-type enzyme represents a product complex after dissociation of the polyamine coproduct. Taken together, these structures provide snapshots of the reaction coordinate of acetylpolyamine hydrolysis and are consistent with a mechanism in which tandem histidine residues H136 and H137 serve as general base and general acid catalysts, respectively. The function of the histidine dyad in the HDAC10 mechanism appears to be similar to that in HDAC6, but not HDAC8 in which both functions are served by the second histidine of the tandem pair.

DOI: https://doi.org/10.1021/acs.biochem.0c00936
ACS Synth Biol. 2021 Jan 15.

Exploiting Spermidine N-Hydroxycinnamoyltransferase Diversity and Substrate Promiscuity to Produce Various Trihydroxycinnamoyl Spermidines and Analogues in Engineered Yeast.

Jennifer Perrin, Natalja Kulagina, Marianne Unlubayir, Thibaut Munsch, Inês Carqueijeiro, Thomas Dugé de Bernonville, Johan-Owen De Craene, Marc Clastre, Benoit St-Pierre, Nathalie Giglioli-Guivarc'h, David Gagneul, Arnaud Lanoue, Vincent Courdavault, Sébastien Besseau.

  Trihydroxycinnamoyl spermidines (THCSpd) are plant specialized metabolites with promising pharmacological activities as antifungals, antibacterial, antiviral, and antidepressant drugs. However, their characterization and potential pharmaceutical exploitation are greatly impaired by the sourcing of these compounds, restricted to the pollen of core Eudicot plant species. In this work, we developed a precursor-directed biosynthesis of THCSpd in yeast using a dual enzymatic system based on 4-coumarate-CoA ligases (4CL) and spermidine N-hydroxycinnamoyltransferases (SHT). The system relies on the yeast endogenous spermidine pool and only requires hydroxycinnamic acids as exogenous precursors. By exploring 4CL isoforms and SHT diversity among plants, we have driven the production of 8 natural THCSpd, using single or mixed hydroxycinnamic acid precursors. Substrate promiscuities of 4CL and SHT were genuinely exploited to produce 8 new-to-nature THCSpd from exotic hydroxycinnamic and dihydrohydroxycinnamic acids, together with 3 new-to-nature THCSpd containing halogenated hydroxycinnamoyl moieties. In this work, we established a versatile and modular biotechnological production platform allowing the tailor-made THCSpd synthesis, constituting pioneer metabolic engineering for access to these valuable natural products.

Keywords:  4-coumarate-CoA ligase; N-hydroxycinnamoyltransferase; phenolamides; precursor-directed biosynthesis; trihydroxycinnamoyl spermidines; yeast engineering

DOI:  https://doi.org/10.1021/acssynbio.0c00391
Metabolomics. 2021 01 11. 17(1): 9

Plasma metabolites associated with chronic kidney disease and renal function in adults from the Baltimore Longitudinal Study of Aging.

Yuko Yamaguchi, Marta Zampino, Ruin Moaddel, Teresa K Chen, Qu Tian, Luigi Ferrucci, Richard D Semba.

   INTRODUCTION: Chronic kidney disease (CKD) is an important cause of disability and death, but its pathogenesis is poorly understood. Plasma metabolites can provide insights into underlying processes associated with CKD.
OBJECTIVES: To clarify the relationship of plasma metabolites with CKD and renal function in human.
METHODS: We used a targeted metabolomics approach to characterize the relationship of 450 plasma metabolites with CKD and estimated glomerular filtration rate (eGFR) in 616 adults, aged 38-94 years, who participated in the Baltimore Longitudinal Study of Aging.
RESULTS: There were 74 (12.0%) adults with CKD. Carnitine, acetylcarnitine, propionylcarnitine, butyrylcarnitine, trigonelline, trimethylamine N-oxide (TMAO), 1-methylhistidine, citrulline, homoarginine, homocysteine, sarcosine, symmetric dimethylarginine, aspartate, phenylalanine, taurodeoxycholic acid, 3-indolepropionic acid, phosphatidylcholines (PC).aa.C40:2, PC.aa.C40:3, PC.ae.C40:6, triglycerides (TG) 20:4/36:3, TG 20:4/36:4, and choline were associated with higher odds of CKD in multivariable analyses adjusting for potential confounders and using a false discovery rate (FDR) to address multiple testing. Six acylcarnitines, trigonelline, TMAO, 18 amino acids and biogenic amines, taurodeoxycholic acid, hexoses, cholesteryl esters 22:6, dehydroepiandrosterone sulfate, 3-indolepropionic acid, 2 PCs, 17 TGs, and choline were negatively associated with eGFR, and hippuric acid was positively associated with eGFR in multivariable analyses adjusting for potential confounders and using a FDR approach.
CONCLUSION: The metabolites associated with CKD and reduced eGFR suggest that several pathways, such as the urea cycle, the arginine-nitric oxide pathway, the polyamine pathway, and short chain acylcarnitine metabolism are altered in adults with CKD and impaired renal function.

Keywords:  Aging; Biomarker; Chronic kidney disease; Glomerular filtration rate; Mass spectrometry; Metabolomics

DOI:  https://doi.org/10.1007/s11306-020-01762-3
J Biol Chem. 2021 Jan 08. pii: S0021-9258(21)00041-7. [Epub ahead of print] 100274

Adipocyte-specific GPRC6A ablation promotes diet-induced obesity by inhibiting lipolysis.

Satoru Mukai, Akiko Mizokami, Takahito Otani, Tomomi Sano, Miho Matsuda, Sakura Chishaki, Jing Gao, Tomoyo Kawakubo-Yasukochi, Ronghao Tang, Takashi Kanematsu, Hiroshi Takeuchi, Eijiro Jimi, Masato Hirata.

  The G protein-coupled receptor GPRC6A regulates various physiological processes in response to its interaction with multiple ligands such as extracellular basic amino acids, divalent cations, testosterone, and the uncarboxylated form of osteocalcin (GluOC). Global ablation of GPRC6A increases the susceptibility of mice to diet-induced obesity and related metabolic disorders. However, given that GPRC6A is expressed in many tissues and responds to a variety of hormonal and nutritional signals, the cellular and molecular mechanisms underlying the development of metabolic disorders in conventional knockout mice have remained unclear. On the basis of our previous observation that long-term oral administration of GluOC markedly reduced adipocyte size and improved glucose tolerance in wild-type mice, we examined whether GPRC6A signaling in adipose tissue might be responsible for prevention of metabolic disorders. We thus generated adipocyte-specific GPRC6A knockout mice, and we found that these animals manifested increased adipose tissue weight, adipocyte hypertrophy, and adipose tissue inflammation when fed a high-fat, high-sucrose diet compared with control mice. These effects were associated with reduced lipolytic activity due to down-regulation of lipolytic enzymes such as adipose triglyceride lipase (ATGL) and hormone-sensitive lipase in adipose tissue of the conditional knockout mice. Given that, among GPR6CA ligands tested, GluOC and ornithine increased the expression of ATGL in cultured 3T3-L1 adipocytes in a manner dependent on GPRC6A, our results suggest that the constitutive activation of GPRC6A signaling in adipocytes by GluOC or ornithine plays a key role in adipose lipid handling and the prevention of obesity and related metabolic disorders.

Keywords:  G protein–coupled receptor; GPRC6A; adipocyte; adipose triglyceride lipase (ATGL); forkhead box O1 (FoxO1); lipolysis; obesity

DOI:  https://doi.org/10.1016/j.jbc.2021.100274