bims-polyam 2021-08-01 papers

J Clin Endocrinol Metab. 2021 Jul 28. pii: dgab554. [Epub ahead of print]

A blood-based polyamine signature associated with MEN1 duodenopancreatic neuroendocrine tumor progression.

PURPOSE: Duodenopancreatic neuroendocrine tumors (dpNETs) frequently occur in patients with Multiple Endocrine Neoplasia Type 1 (MEN1), and metastatic dpNET is the primary cause of disease-related mortality. There is a need for biomarkers that can identify patients with MEN1-related dpNETs that are at high risk of developing distant metastasis. Polyamines have tumor promoting roles in several cancer types. We hypothesized that MEN1-dpNET-related disease progression is associated with elevated levels of circulating polyamines.
EXPERIMENTAL DESIGN: Through an international collaboration between MD Anderson Cancer Center (MDACC), the National Institutes of Health (NIH), and the University Medical Center Utrecht (UMCU), plasma polyamine levels were assessed using mass spectrometry in a total of 84 patients with MEN1 (20 with distant metastatic dpNETs (cases) and 64 with either indolent dpNETs or no dpNETs (controls)). A mouse model of MEN1-pNET, Men1 fl/flPdx1-Cre Tg, was used to test time-dependent changes in plasma polyamines associated with disease progression.
RESULTS: A 3-marker plasma polyamine signature (3MP: n-acetylputrescine, acetylspermidine, and diacetylspermidine) distinguished patients with metastatic dpNETs from controls in an initial set of plasmas from the three participating centers. The fixed 3MP yielded an AUC of 0.84 (95% CI: 0.62-1.00) with 66.7% sensitivity at 95% specificity for distinguishing cases from controls in an independent test set from MDACC. In Men1 fl/flPdx1-Cre Tg mice, the 3MP was elevated early and remained high during disease progression.
CONCLUSIONS: Our findings provide a basis for prospective testing of blood-based polyamines as a potential means for monitoring patients with MEN1 for harboring or developing aggressive disease.

Keywords: biomarker; pancreatic neuroendocrine tumors; polyamines

DOI: https://doi.org/10.1210/clinem/dgab554

Cancer Chemother Pharmacol. 2021 Jul 26.

Arginine depriving enzymes: applications as emerging therapeutics in cancer treatment.

Neha Kumari, Saurabh Bansal.

Cancer is the second leading cause of death globally. Chemotherapy and radiation therapy and other medications are employed to treat various types of cancer. However, each treatment has its own set of side effects, owing to its low specificity. As a result, there is an urgent need for newer therapeutics that do not disrupt healthy cells' normal functioning. Depriving nutrient or non/semi-essential amino acids to which cancerous cells are auxotrophic remains one such promising anticancer strategy. L-Arginine (Arg) is a semi-essential vital amino acid involved in versatile metabolic processes, signaling pathways, and cancer cell proliferation. Hence, the administration of Arg depriving enzymes (ADE) such as arginase, arginine decarboxylase (ADC), and arginine deiminase (ADI) could be effective in cancer therapy. The Arg auxotrophic cancerous cells like hepatocellular carcinoma, human colon cancer, leukemia, and breast cancer cells are sensitive to ADE treatment due to low expression of crucial enzymes argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), and ornithine transcarbamylase (OCT). These therapeutic enzyme treatments induce cell death through inducing autophagy, apoptosis, generation of oxidative species, i.e., oxidative stress, and arresting the progression and expansion of cancerous cells at certain cell cycle checkpoints. The enzymes are undergoing clinical trials and could be successfully exploited as potential anticancer agents in the future.

Keywords: Arginase; Arginine decarboxylase; Arginine deiminase; Argininosuccinate synthetase; Auxotrophic cancer; Deprivation therapy; Therapeutic enzyme

DOI: https://doi.org/10.1007/s00280-021-04335-w

Inorganics (Basel). 2019 Aug;pii: 101. [Epub ahead of print]7(8):

Human acireductone dioxygenase (HsARD), cancer and human health: Black hat, white hat or gray?

Xinyue Liu, Thomas C Pochapsky.

Multiple factors involving the methionine salvage pathway (MSP) and polyamine biosynthesis have been found to be involved in cancer cell proliferation, migration, invasion and metastasis. This review summarizes the relationships of the MSP enzyme acireductone dioxygenase (ARD), the ADI1 gene encoding ARD and other gene products (ADI1GP) with carcinomas and carcinogenesis. ARD exhibits structural and functional differences depending upon the metal bound in the active site. In the penultimate step of the MSP, the Fe2+ bound form of ARD catalyzes the on-pathway oxidation of acireductone leading to methionine, whereas Ni2+ bound ARD catalyzes an off-pathway reaction producing methylthiopropionate and carbon monoxide, a biological signaling molecule and anti-apoptotic. The relationship between ADI1GP, MSP and polyamine synthesis are discussed, along with possible role(s) of metal in modulating the cellular behavior of ADI1GP and its interactions with other cellular components.

Keywords: AD11; S-adenosylmethionine (SAM); enolase phosphatase 1 (ENOPH1); matrix metalloproteinase MT1 (MT1-MMP); methionine; methionine salvage pathway; methylthioadenosine (MTA); nickel-dependent enzyme; polyamine

DOI: https://doi.org/10.3390/inorganics7080101

Chemometr Intell Lab Syst. 2021 Oct 15. 217 104394

Identification of Food Compounds as inhibitors of SARS-CoV-2 main protease using molecular docking and molecular dynamics simulations.

Vijay H Masand, Md Fulbabu Sk, Parimal Kar, Vesna Rastija, Magdi E A Zaki.

SARS-CoV-2 has rapidly emerged as a global pandemic with high infection rate. At present, there is no drug available for this deadly disease. Recently, Mpro (Main Protease) enzyme has been identified as essential proteins for the survival of this virus. In the present work, Lipinski's rules and molecular docking have been performed to identify plausible inhibitors of Mpro using food compounds. For virtual screening, a database of food compounds was downloaded and then filtered using Lipinski's rule of five. Then, molecular docking was accomplished to identify hits using Mpro protein as the target enzyme. This led to identification of a Spermidine derivative as a hit. In the next step, Spermidine derivatives were collected from PubMed and screened for their binding with Mpro protein. In addition, molecular dynamic simulations (200 ns) were executed to get additional information. Some of the compounds are found to have strong affinity for Mpro, therefore these hits could be used to develop a therapeutic agent for SARS-CoV-2.

Keywords: COVID-19; Food compounds; Free energy; MD Simulation; Mpro; SARS-CoV-2; Spermidine; Virtual screening

DOI: https://doi.org/10.1016/j.chemolab.2021.104394

Commun Biol. 2021 Jul 29. 4(1): 927

Cryo-EM structures of inhibitory antibodies complexed with arginase 1 provide insight into mechanism of action.

Human Arginase 1 (hArg1) is a metalloenzyme that catalyzes the hydrolysis of L-arginine to L-ornithine and urea, and modulates T-cell-mediated immune response. Arginase-targeted therapies have been pursued across several disease areas including immunology, oncology, nervous system dysfunction, and cardiovascular dysfunction and diseases. Currently, all published hArg1 inhibitors are small molecules usually less than 350 Da in size. Here we report the cryo-electron microscopy structures of potent and inhibitory anti-hArg antibodies bound to hArg1 which form distinct macromolecular complexes that are greater than 650 kDa. With local resolutions of 3.5 Å or better we unambiguously mapped epitopes and paratopes for all five antibodies and determined that the antibodies act through orthosteric and allosteric mechanisms. These hArg1:antibody complexes present an alternative mechanism to inhibit hArg1 activity and highlight the ability to utilize antibodies as probes in the discovery and development of peptide and small molecule inhibitors for enzymes in general.

DOI: https://doi.org/10.1038/s42003-021-02444-z