ADP-ribosyl protein lyase

Early studies of ADP-ribose polymer metabolism concluded that PARG was unable to remove the protein proximal ADPR residue from acceptor proteins. This led to the isolation of an ADP-rlbosyl protein lyase that catalyzes removal of the protein proximal ADPR residue linked to the acceptor protein. Although this enzyme was discovered many years ago, it has received very little attention and consequently its structure function relationships and role in ADPR polymer metabolism are still poorly understood. Additional questions have been raised by recent studies that indicate that PARG can catal removal of protein proximal ADPR residues linked to carboxylate groups of histone HI. It is possible that the property of both enzymes to catalyze removal of these residues represents redundancy in function or that specific polymer acceptor proteins require different enzymes to catalyze removal. 

Ame JC, Jacobson EL, Jacobson MK. ADP-ribose polymer metabolism. In de Murcia G, Shall S, eds. From DNA Damage and Stress Sig ling to Cell Death Poly ADP-Ribosylation Reactions. Oxford, New York Oxford University Press, 2000 1-34. 

Ueda K, Hayaishi O et al. ADP-ribosyl protein lyase. Purification, properties and identification of the product. J Biol Chem 1984 259(2) 986-95. 

Kreimeyer A, Wielckens K, Adamietz P et al. DNA repair-associated ADPribosylation in vivo. Modification of histone HI difiers from that of the principal acceptor proteins. J Biol Chem 1984 259(2) 890-6. 

Cervantes-Laurean D, Jacobson EL, Jacobson MK. Glycation and glycoxidation of histones by ADP-ribose. J Biol Chem 1996 271(18) 10461-10469. 

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The enzyme catalyzing the addition of ADP-ribose units onto the histones and itself is poly(ADP-ribose) polymerase or synthetase. Poly(ADP-ribose) polymerase is a nuclear, DNA-dependent enzyme that is stimulated by DNA breaks [302]. This property of the enzyme would target its action to sites that have DNA strand breaks (regions of the genome involved in replication, repair, recombination). The enzyme is associated with chromatin areas and perichromatin regions in interphase Chinese hamster ovary cells [312]. Degradation of the ADP-ribose polymer is catalyzed by the nuclear enzyme poly(ADP-ribose) glycohydrolase and ADP-ribosyl protein lyase. 

ADP-protein lyase. The single ADP-ribose residue still attached to protein after glycohydrolase action on the polymer can be cleaved by ADP-ribosyl protein lyase. The enzyme is specific for ester linkages to the protein. [Clinical note Williams and collaborators at the University of Texas Health Center have described the case... 

Figure 2. Enzymatic degradation of poly(ADP-ribose).The arrows indicate the covalent bonds that are cleaved by poly(ADP-ribose) glycohydrolase ( ), ADP-ribosyl protein lyase (-- ), and phosphodiesterase (Jl). The reader can work out what the respective reaction products would be in each case (refer also to Figure 1).

A third enzyme, ADP-ribosyl protein lyase, catalyzes the nonhydrolytic cleavage of protein proximal ADPR residues yielding the unique nucleotide ADP-3"-deoxy-pentos-2"-ulose (ADP-DP). In addition to the basic enzymology shown in Figure 1, related enzyme activities... 

PolyfADP-ribose) is synthesized by PARP-1 and hydrolyzed by enzymes known as polyfADP-ribose) glycohydrolase (PARC), phosphodiesterases (PDases) and ADP-ribosyl protein lyase. Among these, PARC serves as an enzyme that hydrolyzes poly(ADP-ribose) chains quite efficiendy, including the branched pordon, and finally leaves the protein-proximal mono-ADP-ribose molecule, which might be removed by ADP-ribosyl protein lyase or released spontaneously at neutral pH. Such de-modificadon would enable PARP-1 to use the same acceptor protein in a new cycle of poly(ADP-ribos )adon (F 1). 

Figure 1. Metabolism of poly(ADP-ribose). Poly(ADP-ribosyl)ation is a posttranslational modification of acceptor proteins, and poly(ADP-ribose) itself serves as a component of cell struaure. Poly(ADP-ribose) glycohydrolase (PARC) is a main enzyme to degrade poly(ADP-ribose) and forms ADP-ribose as product. Other degrading enzymes ate phosphodiesterase (or pyrophosphatase) and ADP-ribosyl protein lyase.

ADP-3"-Deoxypentos-2"-Ulose. A Novel Product of ADP-Ribosyl Protein Lyase... 

Our previous studies [1,2] revealed that the degradation of poly(ADP-ribosyl) proteins is carried out by consecutive actions of two enzymes, poly(ADP-ribose) giycohydrolase [3, 4] and ADP-ribosyl protein lyase (formerly termed ADP-ribosyl histone splitting enzyme) [5] (Fig. 1). The latter enzyme catalyzes removal of the last proximal ADP-ribosyl residue from acceptor protein. This report presents, after a brief review of ADP-ribosyl histones and the lyase, the identification of the enzymatic split product... 

Fig. 1. Mode of degradation of poly(ADP-ribosyl) protein by poly(ADP-ribose) giycohydrolase and ADP-ribosyl protein lyase...

Fig. 3. AG 1 column chromatography of the reaction product of ADP-ribosyl protein lyase. [Ade- C]ADP-ribosyl histone H2B was treated with the enzyme, and 20% CI3 CCOOH-soluble product was analyzed by chromatography on an AG 1-X2 (formate form) column the column was eluted with a gradient of 0-6 M formic acid. O Ajgo C (cpm/0.9 ml). (Taken from Oka et al. [12])...

Oka J, Ueda K, Hayaishi 0, Komura H, Nakanishi K (1984) ADP-ribosyl protein lyase. J Biol Chem 259 986-995... 

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