Penicillamine-cysteine disulfide

Methionine Homocitrulline Alloisoleucine Penicillamine-cysteine disulfide... 

Penicillamine U Penicillamine disulfide, penicillamine-cysteine disulfide T H... 

Xu et al. [5] described the effect of (z>)-penicillamine on the binding of several antiacetylcholine receptor monoclonal antibodies to the Torpedo acetylcholine receptor. Penicillamine is covalently incorporated into the acetylcholine receptor through SS exchange at the cysteine residues of the a-subunit, altering the antigenic structure of the receptor. This effect on the structure of the native receptor at the neuromuscular junction may be responsible for the establishment of the autoimmune response to the acetylcholine receptor in (i))-penicillamine-induced myasthenia gravis. Cysteine and penicillamine interact to form penicillamine-cysteine mixed disulfide complexes [6] ... 

The rationale for the use of penicillamine in cystinuria is that penicillamine reacts with the poorly soluble cysteine in a thiol-disulfide exchange reaction and forms a relatively water-soluble cysteine-penicillamine mixed disulfide. In cystinuria, the urinary excretion of cystine is used to adjust dosage, although 2 g/day in 4 divided doses usually is employed. 

Fig. 23. Reaction of penicilloic acid (/) with cystine to yield penamaldic acid-cysteine mixed disulfide (//). Subsequent hydrolysis of II yields penicillamine-cysteine mixed disulfide (III) and penaldic acid (IV)...

D-Penicillamine may arise directly from penicilloic acid or through formation of a penicillamine-cysteine mixed disulfide, following a penamaldate rearrangement (Levine 1960 c Yemal et al. 1978). This reaction also occurs with functional derivatives of the alpha-carboxylic group of penicilloic acid (Schneider et al. 1973). The penicillamine determinant may therefore arise in vivo from any penicilloyl conjugate. 

D-penidllamine can promote the elimination of copper (e.g., in Wilson s disease) and of lead ions. It can be given orally. Two additional uses are cystinu-ria and rheumatoid arthritis. In the former, formation of cystine stones in the urinary tract is prevented because the drug can form a disulfide with cysteine that is readily soluble. In the latter, penicillamine can be used as a basal regimen (p. 320). The therapeutic effect may result in part from a reaction with aldehydes, whereby polymerization of collagen molecules into fibrils is inhibited. Unwanted effects are cutaneous damage (diminished resistance to mechanical stress with a tendency to form blisters), nephrotoxicity, bone marrow depression, and taste disturbances. 

Mechanism of Action Asulfhydryl compound with similar properties to those of penicillamine and glutathione that undergoes thiol-disulfide exchange with cysteine to form tiopronin-cysteine, a mixed disulfide. This disulfide is water soluble, unlike cysteine, and does not crystallize in the kidneys. May break disulfide bonds present in bronchial secretions and break the mucus complexes. Therapeutic Effect Decreases cysteine excretion. 

Although such reactions have been known for a long time, it appears a somewhat neglected area of study. Most attention has been on cysteine and its oxidation to the disulfide which is catalyzed by metal ions, in particular CuI[ (see Section 20.2.2.2.2) and FeI,[.81 The likely intermediates in these reactions are metal-cysteine complexes which undergo internal electron transfer. As noted earlier (Section 20.2.2.2.2), penicillamine differs from cysteine in its reactivity and gives rise to mixed valence species. More recently Mn11 has also been found to catalyze the oxidations of Cys and Pen. 

In an effort to decrease the flexibility of the disulfide-bridged enkephalins, penicillamine residues (C, C -dimethylcysteine, Pen) have been introduced in place of the cysteine residues. The D-Pen2-D-Cys5 peptide exhibited substantial 8 receptor activities (Mosberg et al., 1982). Even... 

The oxidation of thiols in the form of L-cysteine, penicillamine, and thioglycollic acid by [Mo(CN)g] in aqueous acidic solution also formed disulfides as final products 111). The reactions show a second-order substrate dependence, and the rates are found to decrease with increasing hydrogen ion concentration. This is attributed to the deprotonation of the —SH and —COOH groups in these thiols prior to electron transfer. The reactions are interpreted in terms of outer-sphere activation. An explanation for the second-order dependence on thiol concentration involves ion association between the cyano complex and a protonated form of the thiol, followed by reaction of this complex with a second thiol molecule. 

The two most common reactions for the generation of cyclic peptides are (i) disulfide formation between cysteine or penicillamine residues through oxidation, and (ii) lactam formation between the amino and carboxy terminal ends (head-to-taU cyclization), the annino terminus and the side chain of an aspartic or glutanoic add residue, or between the side chains of a lysine (or another diamino acid) and aspartic or glutanoic acid residues. A special mode of the second type is backbone cyclization between an amino group (N-terminal or side chain) and a carboxyalkylated backbone nitrogen. Both reactions have been used to generate cyclic peptide libraries. 

Improved syntheses for [Mo(CN)8]3 salts based on the use of NaN02 in mineral acid as oxidant have appeared nitrosonium ion, NO+, is believed to be the active agent in this proton-assisted reaction.650 Thiols such as L-cysteine, penicillamine, and thioglycolic acid are oxidized to disulfides by [Mo(CN)g]3, with concomitant formation of [Mo(CN)8]4 kinetics studies of these reactions have been reported.651 The structural and chemical properties of [Mo(CN)8]3 and related species have been reviewed.652... 

D-penicillamine (D-3-mercaptovaline, Cuprimine), a breakdown product of penicillin, was, after the discovery of its chelating properties of copper ion (Fig. 2-6), introduced as an antidote to copper poisoning. It was also found useful in the treatment of Wilson s disease, where excess copper accumulation causes liver cell damage. Heavy metal poisoning treatment is not limited to copper. Mercury and lead poisoning are also successfully reversed. Formation of cysteine calculi (cystinuria) can also be reversed with penicillamine by forming a soluble disulfide compound. 

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