Antibody decarboxylases

Figure 3 compares the proficiencies (kcat/K]v[/kun) of ODCase, several other enzyme decarboxylases [2], and some antibody decarboxylases [3]. The proficiencies of the decarboxylase enzymes, including a variety of amino acid decarboxylases, are nearly equal. Many decarboxylases employ iminium intermediates formed by reaction of an amino acid with a cofactor such as pyruvoyl or pyridoxal, or by reaction of a -keto ester with an active-site lysine residue. These intermediates have been found to be so reactive that the... 

Ando-Yamamoto, M., Hayashi, H., Sugiyama, T., Fukui, H., Watanabe, T., and Wada, H. (1987). Purification of L-dopa decarboxylase from rat liver and production of polyclonal and monoclonal antibodies against it. J. Biochem. 101 405-414. 

Fig. 44 Pathways for uridylate biosynthesis. Mutants lacking enzymes PRTase or ODCase can complete a route to UMP provided by an antibody orotate decarboxylase in conjunction with the naturally occurring uracil PRTase. Decarboxylation of orotic acid [135] is thought to proceed through the transition state [136], for which the hapten [137] was developed (Smiley and Benkovic, 1994).

This situation is largely due to the rise of type 2 DM which now accounts for 85-90% of all cases of DM type 1 DM in which antibodies directed at the enzyme glutamic acid decarboxylase (GAD) attack and destroy the insulin-producing (3 cells... 

Igarashi, K., Kaneda, M., Yamaji, A., Saido, T.C., Kikkawa, U., Qno, Y., Inoue, K., and Umeda, M., 1995, A novel phosphatidylserine-binding peptide motif defined by an anti-idiotypic monoclonal antibody. Localization of phosphatidylserine-specific binding sites on protein kinase C and phosphatidylserine decarboxylase. J. Biol. Chem. 270 29075-29078. 

Type 1 diabetes mellitus occurred after 5 months treatment with etanercept for juvenile rheumatoid arthritis in a 7-year-old girl (389). Antiglutamic acid decarboxylase antibodies were positive both before and during treatment, suggesting that etanercept may have prematurely triggered an underlying disease. 

In three middle-aged patients, diabetes was diagnosed after 3-7 months of treatment with interferon alfa-2b and ribavirin, and two presented with severe ketoacidosis (534,535). There was a family history of diabetes in one patient and two had high titers of glutamic acid decarboxylase antibodies before treatment. One patient never had diabetes-related serum autoantibodies before or after interferon alfa therapy. All three required permanent insulin treatment despite withdrawal of interferon alfa. 

In a randomized trial in 74 patients with chronic hepatitis C treated with interferon alfa-2b and ribavirin, plus placebo or amantadine, two developed glutamic acid decarboxylase (GAD) autoantibodies, but none developed IA-2 or insulin autoantibodies (543). One had an increased titer of GAD autoantibodies during a first sequence of interferon alfa monotherapy, then a further rise during subsequent combination therapy, and finally developed diabetes mellitus after 5 months of treatment. The authors suggested that repetitive treatment with interferon alfa could increase the risk of type 1 diabetes in patients previously positive for islet antibodies. 

The exact mechanisms of tacrolimus-induced diabetes are unknown. In one renal transplant patient with genetic susceptibility, tacrolimus was associated with insulin-dependent diabetes mellitus and the simultaneous occurrence of anti-glutamic acid decarboxylase antibody (1096). Within 2 months after conversion from tacrolimus to ciclosporin, the antibody was no longer detected and the patient s insulin requirements fell dramatically. Tacrolimus-induced direct beta cell toxicity, with... 

Yoshioka K, Sato T, Okada N, Ishii T, Imanishi M, Tanaka S, Kim T, Sugimoto T, Fujii S. Post-transplant diabetes with anti-glutamic acid decarboxylase antibody during tacrolimus therapy. Diabetes Res Clin Pract 1998 42(2) 85-9. 

One of the earliest published attempts to create antibodies with catalytic activity had as its goal the generation of a transaminase. Raso and Stollar prepared V-(5-phosphopyridoxyl)-3 -amino-L-tyrosine 154 as a mimic of the Schiff s base intermediate that is formed during the pyridoxal-dependent transamination of tyrosine and showed that it was a site-directed inhibitor of the enzymes tyrosine transaminase and tyrosine decarboxylase.132 Partially purified polyclonal antibodies, elicited against y-globulin conjugates of the hapten, recognized both the... 

Antibodies to islet cells, insulin, and glutamic acid decarboxylase are present in many patients with newly diagnosed type 1 diabetes. In... 

The most definitive laboratory test to distinguish type 1 from type 2 diabetes is the C-peptide assay, which is a measure of endogenous insulin production. With type 2 diabetes, proinsulin can be split into insulin and C-peptide lack of C-peptide indicates type 1 diabetes. The presence of anti-islet antibodies (to glutamic acid decarboxylase, insulinoma associated peptide-2 or insulin) or absence of insulin resistance (determined by a glucose tolerance test) is also suggestive of type 1. 

In this case, which was marked by three autoimmune complications (insulin-dependent diabetes mellitus, myositis, and myasthenia gravis) in a single patient, a retrospective analysis of the patient s serum before aldesleukin therapy showed the presence of antibodies against glutamic acid decarboxylase, insulin, islet cell antigen, and striated muscle, but was negative for acetylcholine receptor antibodies. Immune stimulation by aldesleukin was... 

A 32-year-old woman with previous autoimmune disorders and a susceptible HLA haplotype developed diabetes with newly positive glutamic acid decarboxylase antibody after taking tacrolimus for 5 months (43). 

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