Adenosine deaminase transition state

FIGURE 16.8 (a) Phosphoglycolohydroxamate is an analog of the enediolate transition state of the yeast aldolase reaction, (b) Purine riboside, a potent inhibitor of the calf intestinal adenosine deaminase reaction, binds to adenosine deaminase as the 1,6-hydrate. The hydrated form of purine riboside is an analog of the proposed transition state for the reaction. 

Figure 2. Transition-state analogs of a) adenosine deaminase, b) sucrase (and other glucosidases), and c) carboxypeptidase A.

Likely Transition State in the Adenosine Deaminase Reaction... 

The adenosine deaminase inhibitor pentostatin is a natural product derived from Streptomyces and structurally it resembles the transition state of adenosine as it is hydrolyzed by adenosine deaminase. 

Coformycin (4.11) is a transition state analogue that competitively inhibits the enzyme adenosine monophosphate (AMP) deaminase (Scheme 4.12). AMP deaminase... 

Frick, L., Mac Neela J.P., and Wolfenden, R. 1987. Transition state stabilization by deaminases. Rates of nonenzymic hydrolysis of adenosine and cytidine. Bioorg. Chem. 15 100-108. 

Of considerable interest in relation to the results of Linschitz Connolly was the subsequent finding of Wolfenden et al. 161) that the photochemical adduct of methanol to purine ribonucleoside is a potent inhibitor of adenosine deaminase, in large part because of its structural resemblance to the presumed transition state intermediate involved in the deaminase reaction. 

Wilson, D. K., Rudolph, F. B., and Quiocho, F. A. Atomic structure of adenosine deaminase complexed with a transition-state analog understanding catalysis and immunodeficiency mutations. Science 252, 1278-1284 (1991). 

Kati, W. M., Wolfenden, R. Contribution of a single hydroxyl group to transition-state discrimination by adenosine deaminase evidence for an entropy trap mechanism. Biochemistry 1989, 28, 7919-7927. 

Pentostatin is a purine antimetabolite. It is a potent transition-state inhibitor of the enzyme adenosine deaminase (ADA) that leads to cytotoxicity because of elevated intracellular levels of dATP that can block DNA synthesis through inhibition of ribonucleotide reductase. Pentostatin can also inhibit RNA synthesis as well as cause increased DNA damage. It is indicated in the treatment for both untreated and alpha-interferon-refractory hairy-cell leukemia and as palliative therapy of chronic lymphocytic leukemia, prolympho-cytic leukemia and cutaneous T-cell lymphoma. 

Adenosine deaminase is the enzyme that hydrolyzes adenosine (or deoxyadenosine) to inosine (or deoxyinosine) and is important for purine metabolism. High levels of adenosine are toxic to B cells of the immune system and can result in an immunocompromised state. Also, people who lack the gene for adenosine deaminase have the genetic condition of severe combined immunodeficiency and are extremely susceptible to opportunistic infections. Many cancer and antiviral agents also are degraded by this enzyme hence, there is a role tor the development of inhibitors of this enzyme (26). The mechanism proposed for adenosine deaminase is a nucleophilic attack of water at the 6-position of the purine base to form a tetrahedral intermediate (Fig. 5.13). The transition state presumably resembles this intermediate. 

Evans BE, Wolfenden RJ. A potential transition-state analogue for adenosine deaminase. J Am Chem Soc 1970 92 4751-4752. 

D. K. Wilson, E B. Rudolph, and F. A. Quiocho, Science, 252,1278 (1991). Atomic Structure of Adenosine Deaminase Complexed with a Transition-State Analog Understanding Catalysis and Immunodeficiency Mutations. 

Produced by Strepcomyces tmcibioticus potent transition state inhibitor of adenosine deaminase used in treatment of a-intetferon-refrac-tive hairy cell leukemia. 

Analogs of tetrahedral transition states - Adenosine deaminase catalyzes the hydrolysis of adenosine (1) to inosine (3), probably via a tetrahedral-like transition state formed by the attack of water (2). 1,6-Dihydro-6-hydro3Qr-... 

Figure 21.12 Mimicking of transition state of adenosine deaminase by pentostatin.

---