scholarly journals Amino Acid Degrading Enzymes and Autophagy in Cancer Therapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Ziyu Wang ◽  
Qinghong Xie ◽  
Haifeng Zhou ◽  
Min Zhang ◽  
Jie Shen ◽  
...  
Keyword(s):  
Amino Acid ◽  
Therapeutic Strategy ◽  
Lymphoblastic Leukemia ◽  
Arginine Deiminase ◽  
Amino Acid Deprivation ◽  
Degrading Enzymes ◽  
Evolutionarily Conserved ◽  
Lysine Oxidase ◽  
Potential Cancer ◽  
Catabolic Process

Recently, there has been renewed interest in metabolic therapy for cancer, particularly in amino acid deprivation by enzymes. L-asparaginase was approved for the treatment of acute lymphoblastic leukemia by the U.S. Food and Drug Administration. Arginine deiminase and recombinant human arginase have been developed into clinical trials as potential cancer therapeutic agents for the treatment of arginine-auxotrophic tumors. Moreover, other novel amino acid degrading enzymes, such as glutaminase, methionase, lysine oxidase, phenylalanine ammonia lyase, have been developed for the treatment of malignant cancers. One of the greatest obstacles faced by anticancer drugs is the development of drug resistance, which is reported to be associated with autophagy. Autophagy is an evolutionarily conserved catabolic process that is responsible for the degradation of dysfunctional proteins and organelles. There is a growing body of literature revealing that, in response to metabolism stress, autophagy could be induced by amino acid deprivation. The manipulation of autophagy in combination with amino acid degrading enzymes is actively being investigated as a potential therapeutic approach in preclinical studies. Importantly, shedding light on how autophagy fuels tumor metabolism during amino acid deprivation will enable more potential combinational therapeutic strategies. This study summarizes recent advances, discussing several potential anticancer enzymes, and highlighting the promising combined therapeutic strategy of amino acid degrading enzymes and autophagy modulators in tumors

Amino Acid Degrading Enzymes and their Application in Cancer Therapy

2019 ◽  
Vol 26 (3) ◽  
pp. 446-464 ◽  
Author(s):  
Vadim S. Pokrovsky ◽  
Olga E. Chepikova ◽  
Denis Zh. Davydov ◽  
Andrey A. Zamyatnin Jr ◽  
Alexander N. Lukashev ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Cancer Therapy ◽  
Cancer Treatment ◽  
Arginine Deiminase ◽  
In Vivo Studies ◽  
Degrading Enzymes ◽  
Essential Components

Background:Amino acids are essential components in various biochemical pathways. The deprivation of certain amino acids is an antimetabolite strategy for the treatment of amino acid-dependent cancers which exploits the compromised metabolism of malignant cells. Several studies have focused on the development and preclinical and clinical evaluation of amino acid degrading enzymes, namely L-asparaginase, L-methionine γ-lyase, L-arginine deiminase, L-lysine α-oxidase. Further research into cancer cell metabolism may therefore define possible targets for controlling tumor growth.Objective:The purpose of this review was to summarize recent progress in the relationship between amino acids metabolism and cancer therapy, with a particular focus on Lasparagine, L-methionine, L-arginine and L-lysine degrading enzymes and their formulations, which have been successfully used in the treatment of several types of cancer.Methods:We carried out a structured search among literature regarding to amino acid degrading enzymes. The main aspects of search were in vitro and in vivo studies, clinical trials concerning application of these enzymes in oncology.Results:Most published research are on the subject of L-asparaginase properties and it’s use for cancer treatment. L-arginine deiminase has shown promising results in a phase II trial in advanced melanoma and hepatocellular carcinoma. Other enzymes, in particular Lmethionine γ-lyase and L-lysine α-oxidase, were effective in vitro and in vivo.Conclusion:The findings of this review revealed that therapy based on amino acid depletion may have the potential application for cancer treatment but further clinical investigations are required to provide the efficacy and safety of these agents.

Amino Acids Sequence-based Analysis of Arginine Deiminase from Different Prokaryotic Organisms: An In Silico Approach

2020 ◽  
Vol 14 (3) ◽  
pp. 235-246
Author(s):  
Sara Abdollahi ◽  
Mohammad H. Morowvat ◽  
Amir Savardashtaki ◽  
Cambyz Irajie ◽  
Sohrab Najafipour ◽  
...  
Keyword(s):  
Amino Acid ◽  
Physicochemical Properties ◽  
Sequence Alignment ◽  
Multiple Sequence Alignment ◽  
In Silico ◽  
Bacterial Species ◽  
Arginine Deiminase ◽  
Antitumor Effects ◽  
Multiple Sequence ◽  
In Silico Studies

Background: Arginine deiminase is a bacterial enzyme, which degrades L-arginine. Some human cancers such as hepatocellular carcinoma (HCC) and melanoma are auxotrophic for arginine. Therefore, PEGylated arginine deiminase (ADI-PEG20) is a good anticancer candidate with antitumor effects. It causes local depletion of L-arginine and growth inhibition in arginineauxotrophic tumor cells. The FDA and EMA have granted orphan status to this drug. Some recently published patents have dealt with this enzyme or its PEGylated form. Objective: Due to increasing attention to it, we aimed to evaluate and compare 30 arginine deiminase proteins from different bacterial species through in silico analysis. Methods: The exploited analyses included the investigation of physicochemical properties, multiple sequence alignment (MSA), motif, superfamily, phylogenetic and 3D comparative analyses of arginine deiminase proteins thorough various bioinformatics tools. Results: The most abundant amino acid in the arginine deiminase proteins is leucine (10.13%) while the least amino acid ratio is cysteine (0.98%). Multiple sequence alignment showed 47 conserved patterns between 30 arginine deiminase amino acid sequences. The results of sequence homology among 30 different groups of arginine deiminase enzymes revealed that all the studied sequences located in amidinotransferase superfamily. Based on the phylogenetic analysis, two major clusters were identified. Considering the results of various in silico studies; we selected the five best candidates for further investigations. The 3D structures of the best five arginine deiminase proteins were generated by the I-TASSER server and PyMOL. The RAMPAGE analysis revealed that 81.4%-91.4%, of the selected sequences, were located in the favored region of arginine deiminase proteins. Conclusion: The results of this study shed light on the basic physicochemical properties of thirty major arginine deiminase sequences. The obtained data could be employed for further in vivo and clinical studies and also for developing the related therapeutic enzymes.

scholarly journals Humanizing the yeast origin recognition complex

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Clare S. K. Lee ◽  
Ming Fung Cheung ◽  
Jinsen Li ◽  
Yongqian Zhao ◽  
Wai Hei Lam ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protein Complex ◽  
Origin Recognition Complex ◽  
Specific Binding ◽  
Life Cycles ◽  
Amino Acid Insertion ◽  
Evolutionarily Conserved ◽  
Transcriptional Start Sites ◽  
Eukaryote Genome ◽  
Origin Recognition

AbstractThe Origin Recognition Complex (ORC) is an evolutionarily conserved six-subunit protein complex that binds specific sites at many locations to coordinately replicate the entire eukaryote genome. Though highly conserved in structure, ORC’s selectivity for replication origins has diverged tremendously between yeasts and humans to adapt to vastly different life cycles. In this work, we demonstrate that the selectivity determinant of ORC for DNA binding lies in a 19-amino acid insertion helix in the Orc4 subunit, which is present in yeast but absent in human. Removal of this motif from Orc4 transforms the yeast ORC, which selects origins based on base-specific binding at defined locations, into one whose selectivity is dictated by chromatin landscape and afforded with plasticity, as reported for human. Notably, the altered yeast ORC has acquired an affinity for regions near transcriptional start sites (TSSs), which the human ORC also favors.

scholarly journals Autophagy Modulation in Cancer: Current Knowledge on Action and Therapy

2018 ◽  
Vol 2018 ◽  
pp. 1-18 ◽  
Author(s):  
Mija Marinković ◽  
Matilda Šprung ◽  
Maja Buljubašić ◽  
Ivana Novak
Keyword(s):  
Therapeutic Strategy ◽  
Current Knowledge ◽  
Therapeutic Agents ◽  
Therapeutic Strategies ◽  
Human Diseases ◽  
The Core ◽  
Future Drug ◽  
Autophagic Activity ◽  
Tumor Types ◽  
Catabolic Process

In the last two decades, accumulating evidence pointed to the importance of autophagy in various human diseases. As an essential evolutionary catabolic process of cytoplasmatic component digestion, it is generally believed that modulating autophagic activity, through targeting specific regulatory actors in the core autophagy machinery, may impact disease processes. Both autophagy upregulation and downregulation have been found in cancers, suggesting its dual oncogenic and tumor suppressor properties during malignant transformation. Identification of the key autophagy targets is essential for the development of new therapeutic agents. Despite this great potential, no therapies are currently available that specifically focus on autophagy modulation. Although drugs like rapamycin, chloroquine, hydroxychloroquine, and others act as autophagy modulators, they were not originally developed for this purpose. Thus, autophagy may represent a new and promising pharmacologic target for future drug development and therapeutic applications in human diseases. Here, we summarize our current knowledge in regard to the interplay between autophagy and malignancy in the most significant tumor types: pancreatic, breast, hepatocellular, colorectal, and lung cancer, which have been studied in respect to autophagy manipulation as a promising therapeutic strategy. Finally, we present an overview of the most recent advances in therapeutic strategies involving autophagy modulators in cancer.

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