Serum asparaginase

Several partial purifications of guinea pig serum asparaginase have been reported, beginning with a sevenfold purification by Meister in... 

Several factors are involved in the wide variation in tumor inhibitory activity of asparaginases from different sources (98). One obvious possibility is the rate of clearance of the enzyme from the circulation of the host animal, and Broome (26) was the first to obtain evidence implicating half-life as a factor in antitumor effectiveness. Guinea pig serum asparaginase, for example, has a half-life time of 11-19 hr, while a partially purified yeast asparaginase preparation without antilymphoma activity is almost completely cleared within 30 min. Differences in half-life alone cannot explain the differences in antitumor activity in all cases, however and the question still remains as to what structural features are responsible for rapid or slow clearance. Mashburn and Landin (85) have suggested that differences in half-life time may be related to the isoelectric point of the enzyme, and evidence also exists to support the idea that the tumor inhibitory activity of some asparaginases is related to their K, values (59, 67). 

The answer is b. (Hardman, pp 1268-1269J Asparaginase is an enzyme that catalyzes the hydrolysis of serum asparagine to aspartic acid and ammonia. Major toxicities are related to antigenicity and pancreatitis. In addition, more than 50% of those treated present biochemical evidence of hepatic dysfunction. 

Since the rate constants of bimolecular diffusion-limited reactions in isotropic solution are proportional to T/ these data testify to the fact that the kt values are linearly dependent on the diffusion coefficient D in water, irrespective of whether the fluorophores are present on the surface of the macromolecule (human serum albumin, cobra neurotoxins, proteins A and B of the neurotoxic complex of venom) or are localized within the protein matrix (ribonuclease C2, azurin, L-asparaginase).1 36 1 The linear dependence of the functions l/Q and l/xF on x/t] indicates that the mobility of protein structures is correlated with the motions of solvent molecules, and this correlation results in similar mechanisms of quenching for both surface and interior sites of the macromolecule. 

Amino Acid Systems Glutamine binding sites, 46, 414 labeling of the active site of r-aspartate /3-decarboxylase with yS-chloro-r-ala-nine, 46, 427 active site of r-asparaginase reaction with diazo-4-oxonorvaline, 46, 432 labeling of serum prealbumin with N-bro-moacetyl-L-thyroxine, 46, 435 a pyridoxamine phosphate derivative, 46, 441. 

Disposition Metabolism of pegaspargase appears to be similar to that of L-asparaginase, which is inactivated by serum proteases, as well as immune and reticu-lendothelial systems. 

The presence of asparaginase in guinea pig serum was first reported by Clementi (10), who also noted the absence of this enzyme in the sera of a number of other common mammals including the rat, cat, dog, monkey, and human. The list of animal sera from which asparaginase... 

Lee and Bridges (13) have confirmed the absence of asparaginase in the serum of a variety of animal species and in 25 human sera but have observed that human and sheep sera, themselves devoid of detectable asparaginase activity, enhanced the activity of guinea pig serum (GPS). Other sera did not show this effect with the GPS enzyme, but all the sera enhanced E. coli asparaginase activity. Further work by these authors (47) and by Ho and Jones (48) indicates that the effect results from a nonspecific stabilization by plasma proteins. 

J. D. Broome. Evidence that 1 asparaginase of guinea pig soun is responsible for its anti lymphoma effects. 0. Lymphoma 6C3HED cells cultured in a medium devoid ofMiPwuiniB lose (hear suKCDtibiliiv to the effects of euinea Die serum in vivo. J. Exp Med. 773 121 (1963). 

T. O. Yellin and J. C. Wriston. Antagonism of purified asparaginase from guinea pig serum towards lymphoma. Science 151 998 (1966). 

Most patients who receive asparaginase develop hver function abnormalities, which can be fatal (12). This adverse effect is of major concern in patients who are also taking other hepatotoxic drugs, such as methotrexate and mercaptopurine. Jaundice and increased serum bihr-ubin and transaminases occur often, and hepatomegaly and fatty deposits occur occasionally. 

J. D. Broome. Evidence that the 1-asparaginase activity in guinea pig serum is responsible for its antilymphoma effects. Nature 191 1114 (1961). 

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