bims-polyam 2019-08-25 papers

on Polyamines

Issue of 2019–08–25
six papers selected by
Sebastian J. Hofer, University of Graz and Alexander Ivanov, Engelhardt Institute of Molecular Biology

Predictive value and clinical significance of increased SSAT-1 activity in healthy adults.
Structure and Function of the Acetylpolyamine Amidohydrolase from the Deep Earth Halophile Marinobacter subterrani.
The importance of plasma arginine level and its downstream metabolites in diagnosing prostate cancer.
Metabolomic study on bleomycin and polyhexamethylene guanidine phosphate-induced pulmonary fibrosis mice models.
Urea cycle disorders in Argentine patients: clinical presentation, biochemical and genetic findings.
Corticospinal tract damage in HHH syndrome: a metabolic cause of hereditary spastic paraplegia.

Future Sci OA. 2019 Jul 01. 5(7): FSO400

Predictive value and clinical significance of increased SSAT-1 activity in healthy adults.

Paramjit S Tappia, Andrew W Maksymiuk, Daniel S Sitar, Parveen S Akhtar, Nazrina Khatun, Rahnuma Parveen, Rashiduzzaman Ahmed, Rashid B Ahmed, Brian Cheng, Gina Huang, Horacio Bach, Brett Hiebert, Bram Ramjiawan.

   Aim: Spermidine/spermine N1-acetyltransferase (SSAT-1) regulates cell growth, proliferation and death. Amantadine is converted by SSAT-1 to acetylamantadine (AA). In our earlier studies, although SSAT-1 was activated in patients with cancer, a number of ostensibly healthy adult volunteers had higher than expected AA concentration. This study was therefore undertaken to examine the outlier group.
Materials & methods: A follow up of urine analysis for AA by liquid chromatography-tandem mass spectrometry as well as clinical assessments and additional blood analyses were conducted.
Results: In some of the outlier controls, higher than expected AA concentration was linked to increased serum carcinoembryonic antigen. Clinical and radiographic assessments revealed underlying abnormalities in other cases that could represent premalignant conditions. Hematology tests revealed elevations in white blood cells and platelets, which are markers of inflammation.
Conclusion: High urine concentration of AA could be used as a simple and useful test for screening of cancer in high-risk populations.

Keywords:  SSAT-1; amantadine; biomarkers; cancer screening and diagnostics; early detection

DOI:  https://doi.org/10.2144/fsoa-2019-0023
Biochemistry. 2019 Aug 22.

Structure and Function of the Acetylpolyamine Amidohydrolase from the Deep Earth Halophile Marinobacter subterrani.

Jeremy Daniel Osko, Benjamin W Roose, Stephen A Shinsky, David W Christianson.

Polyamines are small organic cations essential for cellular function in all kingdoms of life. Polyamine metabolism is regulated by enzyme-catalyzed acetylation-deacetylation cycles in similar fashion to the epigenetic regulation of histone function in eukaryotes. Bacterial polyamine deacetylases are particularly intriguing, since these enzymes share the fold and function of eukaryotic histone deacetylases. Recently, acetylpolyamine amidohydrolase from the deep earth halophile Marinobacter subterrani (msAPAH) was described. This Zn2+-dependent deacetylase shares 53% amino acid sequence identity with the acetylpolyamine amidohydrolase from Mycoplana ramosa (mrAPAH) and 22% amino acid sequence identity with the catalytic domain of histone deacetylase 10 from Danio rerio (zebrafish; zHDAC10), the eukaryotic polyamine deacetylase. The X-ray crystal structure of msAPAH, determined in complexes with 7 different inhibitors as well as the acetate coproduct, shows how the chemical strategy of Zn2+-dependent amide hydrolysis and the catalytic specificity for cationic polyamine substrates is conserved in a subterranean halophile. Structural comparisons with mrAPAH reveal that an array of aspartate and glutamate residues unique to msAPAH enable the binding of one or more Mg2+ ions in the active site and elsewhere on the protein surface. Notwithstanding these differences, activity assays with a panel of acetylpolyamine and acetyllysine substrates confirm that msAPAH is a broad-specificity polyamine deacetylase, much like mrAPAH. Broad substrate specificity contrasts with the narrow substrate specificity of zHDAC10, which is highly specific for N8-acetylspermidine hydrolysis. Notably, quaternary structural features govern the substrate specificity of msAPAH and mrAPAH, whereas tertiary structural features govern the substrate specificity of zHDAC10.

DOI: https://doi.org/10.1021/acs.biochem.9b00582
Int Urol Nephrol. 2019 Aug 23.

The importance of plasma arginine level and its downstream metabolites in diagnosing prostate cancer.

Ismail Selvi, Halil Basar, Numan Baydilli, Koza Murat, Ozlem Kaymaz.

   PURPOSE: There is still no certain threshold value of prostate-specific antigen (PSA) for prostate cancer diagnosis. We aimed to investigate the predictive value of arginine and its metabolites for diagnosing prostate cancer in patients with PSA 4-10 ng/ml and evaluate their usefulness as prognostic tumor markers.
METHODS: Seventy-eight patients with a mean age of 64.50 ± 5.49 years were included in our prospective observational study between November 2016 and March 2017. They were divided into two equal groups according to the pathologic results of prostate biopsy (benign vs. malignant). Plasma arginine and ornithine levels were analyzed before biopsy by liquid chromatography-tandem mass spectrometry. ELISA was used for analyzing urinary diacetylspermine.
RESULTS: In PSA-adjusted analysis, the malignant group had lower plasma arginine levels (p = 0.021) and arginine to ornithine ratio (AOR) (p = 0.010), but higher plasma ornithine levels (p = 0.012) and urinary diacetylspermine levels (p < 0.001) as compared with the benign group. While arginine (r = - 0.628, p < 0.001) and AOR (r = - 0.714, p < 0.001) were negatively correlated with D'Amico clinical classification (p < 0.001), ornithine (r = 0.659, p < 0.001) and diacetylspermine (r = 0.710, p < 0.001) were found to be positively correlated (p < 0.001). In multivariate analysis, ornithine [OR 3.264, 95% CI (1.045-10.196), p = 0.042] and diacetylspermine [OR 6.982, 95% CI (2.403-20.290), p < 0.001] were found to be more significant in detection of prostate cancer.
CONCLUSION: Plasma arginine, ornithine, AOR and urinary diacetylspermine levels may be used as molecular markers to predict prostate biopsy outcomes in patients with PSA 4-10 ng/ml. But according to our results, the use of ornithine and diacethylspermine prior to biopsy seems to be the most cost-effective diagnostic strategy.

Keywords:  Arginine; Diacetylspermin; Ornithine; Prostate biopsy; Prostate cancer; Tumor marker

DOI:  https://doi.org/10.1007/s11255-019-02261-8
Metabolomics. 2019 Aug 17. 15(8): 111

Metabolomic study on bleomycin and polyhexamethylene guanidine phosphate-induced pulmonary fibrosis mice models.

Chan Seo, Sung-Hwan Kim, Hyeon-Seong Lee, Moongi Ji, Jeuk Min, Young-Jin Son, In-Hyeon Kim, Kyuhong Lee, Man-Jeong Paik.

   INTRODUCTION: Polyhexamethylene guanidine phosphate (PHMG) has been used as a disinfectant and biocide, and was known to be harmless and non-toxic. However, in 2011, PHMG used as a humidifier disinfectant was reported to be associated with lung diseases, such as, fibrosis in the toxicant studies on pulmonary fibrosis by PHMG. However, no metabolomics study has been performed in PHMG-induced mouse models of pulmonary fibrosis.
OBJECTIVES: We performed a metabolomic study to understand the biochemical events that occur in bleomycin (BLM)- and PHMG-induced mouse models of pulmonary fibrosis using gas chromatography-mass spectrometry (GC-MS), LC-tandem MS, and GC-tandem MS.
RESULTS: The levels of 61 metabolites of 30 amino acids, 13 organic acids, 12 fatty acids, 5 polyamines, and oxidized glutathione were determined in the pulmonary tissues of mice with BLM- and PHMG-induced pulmonary fibrosis and in normal controls. Principal component analysis and partial least squares discriminant analysis used to compare level of these 61 metabolites in pulmonary tissues. Levels of metabolites were significantly different in the BLM and PHMG groups as compared with the control group. In particular, the BLM- and PHMG-induced pulmonary fibrosis models showed elevated collagen synthesis and oxidative stress and metabolic disturbance of TCA related organic acids including fumaric acid by NADPH oxidase. In addition, polyamine metabolism showed severe alteration in the PHMG group than that of the BLM group.
CONCLUSION: This result suggests PHMG will be able to induce pulmonary fibrosis by arginine metabolism and NADPH oxidase signaling.

Keywords:  Bleomycin; Metabolic profiling analysis; Metabolomics; Polyhexamethylene guanidine phosphate; Pulmonary fibrosis; Tandem mass spectrometry

DOI:  https://doi.org/10.1007/s11306-019-1574-6
Orphanet J Rare Dis. 2019 Aug 19. 14(1): 203

Urea cycle disorders in Argentine patients: clinical presentation, biochemical and genetic findings.

Silene M Silvera-Ruiz, José A Arranz, Johannes Häberle, Celia J Angaroni, Miriam Bezard, Norberto Guelbert, Adriana Becerra, Fernanda Peralta, Raquel Dodelson de Kremer, Laura E Laróvere.

   BACKGROUND: The incidence, prevalence, and molecular epidemiology of urea cycle disorders (UCDs) in Argentina remain underexplored. The present study is the first to thoroughly assess the clinical and molecular profiles of UCD patients examined at a single reference center in Argentina.
RESULTS: Forty-nine UCD cases were collected. About half (26/49, 53%) manifested neonatally with classical presentation and had a high mortality (25/26, 96%). Ornithine transcarbamylase deficiency (OTCD) was the most common UCD (26 patients). Argininosuccinate synthetase deficiency (ASSD) was detected in 19 cases, while argininosuccinate lyase deficiency (ASLD) was diagnosed in 4 cases. Molecular genetic analysis revealed 8 private OTC mutations and two large deletion/duplication events in the OTC gene. Most mutations in the ASS1 and ASL genes were recurrent missense changes, and four alterations were novel. The clinical outcome of our UCD cohort was poor, with an overall mortality of 57% (28/49 cases), and a 28% (6/21) disability rate among the survivors.
CONCLUSIONS: Most patients in our case series showed severe neonatal onset, with high morbidity/mortality. We detected in total 19 mutations, most of them recurrent and of high frequency worldwide. Noteworthy, we highlight the presence of a geographic cluster with high prevalence of a point mutation in the ASS1 gene. This study suggests that these disorders may be more frequent than commonly assumed, and stresses the need for increased awareness amongst health professionals and greater availability of diagnostic tools for accurate identification, early diagnosis, and timely treatment.

Keywords:  Argininosuccinate lyase deficiency; Argininosuccinate synthetase deficiency; Hyperammonemia; Ornithine transcarbamylase deficiency; Urea cycle defects

DOI:  https://doi.org/10.1186/s13023-019-1177-3
Orphanet J Rare Dis. 2019 Aug 23. 14(1): 208

Corticospinal tract damage in HHH syndrome: a metabolic cause of hereditary spastic paraplegia.

Giorgia Olivieri, Stefano Pro, Daria Diodato, Matteo Di Capua, Daniela Longo, Diego Martinelli, Enrico Bertini, Carlo Dionisi-Vici.

   BACKGROUND: Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare disorder of urea cycle characterized by progressive pyramidal and cerebellar dysfunction, whose pathophysiology is not yet fully understood. Here we describe the spectrum of the long fibers involvement in HHH syndrome, attempting a correlation between clinical, electrophysiological and neuro-radiological data.
METHODS: Nine HHH patients were longitudinally evaluated by clinical examination, neurophysiological assessment including motor (MEPs), somato-sensory evoked potentials (PESS) and nerve conduction velocity (NCV), brain and spinal cord MRI RESULTS: All patients had pyramidal dysfunction and 3/9 an overt spastic paraplegia. Mild to moderate cerebellar signs were found in 7/9, intellectual disability in 8/9. At lower limbs, MEPs resulted abnormal in 7/8 patients and PESS in 2/8; peripheral sensory-motor neuropathy was found in 1/9. MRI documented atrophic changes in supra-tentorial brain regions in 6/9 patients, cerebellum in 6/9, spinal cord in 3/7.
CONCLUSIONS: A predominant corticospinal dysfunction is evident in HHH syndrome, along with milder cerebellar signs, intellectual disability of variable degree and rare peripheral neuropathy. Phenotypical similarities with other disorders affecting the urea cycle (argininemia and pyrroline-5-carboxylate synthetase deficiency) suggest possible common mechanisms contributing in the maintenance of the corticospinal tract integrity. HHH syndrome phenotype largely overlaps with complex Hereditary Spastic Paraplegias (HSPs), in the list of which it should be included, emphasizing the importance to screen all the unsolved cases of HSPs for metabolic biomarkers.

Keywords:  HHH syndrome; Hereditary spastic paraplegia; Ornithine; Urea cycle defects

DOI:  https://doi.org/10.1186/s13023-019-1181-7