The Arginine Deiminase​: an Anticancer Protein

Arginine deiminase (ADI, EC 3.5.3.6) is an arginine-metabolizing hydrolase that catalyzes the hydrolysis of the amino acid L-arginine to form citrulline and ammonia. This reaction is the first step in the degradation pathway of this amino acid that, ultimately, produces one molecule of ornithine and one of carbamoyl phosphate (the last one then used to produce an ATP molecule). ADI is absent in humans but present in a wide range of bacterial species such as Pseudomonas aeruginosa, Pseudomonas plecoglossicida, Mycoplasma arginini and in parasitic protists. For pathogenic bacteria, ADI is required in arginine dihydrolase pathway for virulence and for energy production under anaerobic conditions.

PictureM6_ADI

The interest in this enzyme is motivated by its potential application as a drug in the amino acids depletion therapy for the treatment of arginine-auxotrophic tumors, such as hepatocellular carcinomas and melanomas. This is one type of targeted therapy for human cancers which are auxotrophic for a particular amino acid. Amino acids degrading enzymes (as, for example, the asparaginase) have been studied for inhibition of tumor cells in vitro. However, their use is sometimes accompanied by serious side-effects. Arginine is an important amino acid involved in the synthesis of peptides and proteins, production of creatine and nitric oxide, and it is present in many metabolic pathways. It is a precursor of different amino acids, neurotransmitters, and also serves as a substrate for two important enzymes, arginase, and nitric oxide synthetase.

Arginine is an indispensable amino acid for children but a semi-essential amino acid in adult humans since many adult somatic cells can synthesize it from citrulline. The enzyme argininosuccinate synthetase (ASS) catalyzes the conversion of citrulline and aspartic acid to argininosuccinate which is then further converted to arginine and fumaric acid by argininosuccinate lyase (ASL). Arginine can be degraded to ornithine by the urea cycle enzyme arginase. Ornithine is then converted back to citrulline by ornithine carbamoyltransferase (OTC) and then recycles back to arginine from citrulline by ASS/ASL. Thus, the ability to regenerate arginine from citrulline depends on the amount/activity of ASS and ASL, which are tightly coupled. The sensitivity of cells to arginine deprivation depends on the ability of ASS and ASL to regenerate arginine from the alternative intermediate (ornithine, citrulline, and argininosuccinate) in the urea cycle.

In collaboration with Dr. Lei Lei Zhu of the group of Prof. Ulrich Schwaneberg (at the RWTH Aachen), we have studied new mutants with an improved catalytic activity of the ADI [1,2]. The molecular modeling study performed by our group pointed out possible structural changes in the protein active site that explain the improved activity.

REFERENCES

  1. L. Zhu, R. Verma, D. Roccatano, Y. Ni, Z.-H. Sun, U. Schwaneberg. A Potential Antitumor Drug (Arginine Deiminase) Reengineered for Efficient Operation under Physiological Conditions. ChemBioChem 11 (5), 691–697 (2010).
  2. L. Zhu, K. L. Tee, D. Roccatano, B. Sonmez, Y. Ni, Z.-H. Sun, U. Schwaneberg. Directed evolution of a potential anti-tumor drug (arginine deiminase) for increased activity at physiological pH. ChemBioChem 11 (5), 691–697 (2010).

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About Danilo Roccatano

I have a Doctorate in chemistry at the University of Roma “La Sapienza”. I led educational and research activities at different universities in Italy, The Netherlands, Germany and now in the UK. I am fascinated by the study of nature with theoretical models and computational. For years, my scientific research is focused on the study of molecular systems of biological interest using the technique of Molecular Dynamics simulation. I have developed a server (the link is in one of my post) for statistical analysis at the amino acid level of the effect of random mutations induced by random mutagenesis methods. I am also very active in the didactic activity in physical chemistry, computational chemistry, and molecular modeling. I have several other interests and hobbies as video/photography, robotics, computer vision, electronics, programming, microscopy, entomology, recreational mathematics and computational linguistics.
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