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Nomenclature for enkephalin degrading peptidases
Life Sciences, Vol. 38, pp. 1151-1153 Printed in the U.S.A.
Pergamon Press
MINIREVIEW
NOMENCLATURE FOR ENKEPHALIN DEGRADING PEPTIDASES Louis B. Hersh Department of Biochemistry University Of Texas Health Science Center Dallas, Texas 75235
Summary The use of trivial names for enkephalin degrading peptidases such as "aminoenkephalinase" and "carboxyenkephalinase" imply a specificity and cellular localization which is not inherent in any of the peptidases implicated in the degradation of endogenous enkephalins. Rather than name these enzymes on the basis of one of their many substrates, it is proposed that they be named according to their general reaction type. Such a nomenclature has already been proposed for the enkephalin degrading endopeptidase 24.11 given the trivial name "enkephalinase". In a recent review article, Dua et al (I) proposed a system for naming enkephalin degrading peptidases. The nomenclature chosen is based on that used for the acetylcholine hydrolyzing enzymes. Acetylcholinesterase is the name given to the brain enzyme which hydrolyzes synaptically released acetylcholine, and pseudocholinesterases are those enzymes which can hydrolyze acetylcholine peripherally. The term "aminoenkephalinase" was proposed for an enzyme which cleaves enkephalins at the Tyr-Gly bond and for which enkephalins are highly specific substrates. The name "carboxyenkephalinase" was proposed for the enzyme which has previously been given the trivial name "enkephalinase" and which cleaves at the Gly-Phe bond of enkephalins. The name "carboxyendopeptidase" was derived from the incorrect classification of this enzyme as a dipeptidylcarboxypeptidase. In addition, the name "endoenkephalinase" was suggested for the dipeptidylaminopeptidase which cleaves enkephalins at the Gly-Gly bond. Lastly, the term "pseudoenkephalinase" is to be used for naming peptidases with broad substrate specificity which hydrolyze enkepb~lins as well as other peptides, which are located both centrally and peripherally. This nomenclature system, although potentially useful when referring specifically to enkephalin metabolism in brain in vivo, may in fact result in confusion rather than clarification of an already confusing nomenclature system. Using the definitions cited above, all of the enkephalin degrading peptidases described in the literature would be classified as "pseudoenkephalinases". The enzymes to be called "aminoenkephalinases" include the en~ephalln degrading aminopeptidase MII described by Hersh (2,3) and purified by Hui et al (4) as well as the aminopeptidase commonly referred to aminopeptidase M (5). Although both of these enzymes have been implicated in the degradation of endogenously released enkephalins in brain, neither 0024-3205/86 $3.00 + .00 Copyright (c) 1986 Pergamon Press Ltd.
1152
Naming Enkephalin Degrading Peptidases
Vol. 38, No. 13, 1986
preferentially utilizes the enkephalins as substrates. The aminopeptidase we designated as aminopeptidase MII has been shown to exhibit a broad specificity with regards to synthetic amino acid beta-naphthylamide substrates (3). In addition the enzyme also utilizes several naturally occurring peptides as substrates including alpha and beta-neo-endorphin (6), alpha and gasm~a-endorphin (2), and probably dynorphin-8 (7). In fact, it has yet to be established that this aminopeptidase is a brain specific peptidase. Aminopeptidase M, which has recently been suggested to be the major enkephalin degrading aminepeptidase in brain (5), is known to have both a broad substrate specificity and a wide tissue distribution (8). Thus, there is no definitive evidence that the aminopeptidase we have named MII acts solely as an enkephalinase in brain, and clearly aminopeptidase M does not fulfill this role. The enzyme to be given the name "carboxyenkephalinase", although initially referred to as a "dipeptidylcarboxypeptidase", has been shown to be a neutral metalloendopeptidase with a specificity for cleavage on the amino side of hydrophobic amino acids (9-11). This enzyme is similar in many respects to a group of bacterial neutral endopeptidases of which thermolysin is the best characterized. The enzyme hydrolyzes a variety of biologically active peptides including angiotensins I and II (12) , neurotensin (9), substance P (13), bradykinin (9), beta lipotropin 61-69 (14), and g ~ m a - e n d o r p h i n (14). In addition, this enzyme exhibits a wide tissue distribution, with brain tissue having a relative low content of the enzyme (15,16). Thus, although this endopeptidase appears to function in the degradation of endogenously released enkephalins in brain (17), it also lacks both the substrate specificity and tissue specificity to be called ~n enkephalinase in the same context as the name acetylcholinesterase is applied. Enzymes are generally classified according to the reaction they catalyze. In the case of peptidases with a rather broad substrate specificity the naming of an enzyme on the basis of a particular peptide substrate can only lead to confusion. For example, assume researchers studying enkephalin degradation use the name "enkephalinase" for the neutral metalloendopeptidase which belongs to the 24.11 classification of endopeptidases. Other researchers studying bradykinin metabolism find the same enzyme and name it "bradykininase", while other groups studying angiotensin I metabolism would name the enzyme "angiotensinase". A vast amount of duplication of publications could occur, and probably already has occurred, due to the variety of names adopted for the same protein. At the present time there is no definitive nomenclature adopted for the enkephalin degrading peptidases. The name "endopeptidase 24.11" proposed by Matsas et al (13) appears to be the most appropriate name for the enkephalin degrading metallo-endopeptidase commonly referred to as "enkephalinase". Similarly the enkephalin degrading aminopeptidase should probably be referred to as aminopeptidase 3.4.11 until it has been fully characterized. The use of these less descriptive terms should help to alleviate the problems encountered when enzymes of a relatively broad substrate specificity are named on the basis of only one of their substrates. On the other hand reference to an enzyme such as endopeptidase 24.11 acting as an "enkephalinase" in vivo would be appropriate provided the proper name of the enzyme were utilized.
Vol. 38, No. 13, 1986
Naming Enkephalln Degrading Peptidases
1153
Acknowledgements T h i s study was supported in part by Grant No. DA02243 from NIDA and Grant No. 1391 from the Welch Foundation, Houston, Texas.
References i. 2. 3. 4. 5. 6. 7. 8. 9. 10. II. 12. 13. 14. 15. 16.
A.K.DUA, C. PINSKY and F.S. LABELLA, Life Sci. 37985-992 (1985). L.B. HERSH, Biochemistry 202345-2350 (1981). L.B. HERSH, J. Neurochem. 441427-1435 (1985). K.-S. HUI, M. HUI and A. LAJTHA, Biochemistry 221062-1067 (1983). C. GROS, B. GIROS and J.-L. SCHWARTZ, Biochemistry 2_~4 2179-2185 (1985). C. ULRICH and L. B. HERSH, Peptides 6 4 7 5 - 4 8 2 (1985). M.G.C. GILLAN, L.E. ROBSON, A.T. MCKNIGHT and H.W. KOSTERLITZ, J. Neurochem. 451034-1042 (1985). F.E. PALMIERI, J.J. PETRELLI and P.E. WARD, Biochem. Parmacol. 34 2309-2317 (1985). J. ALMENOFF, S. WILK and M. ORLOWSKI, Biochem. Biophys. Res. Commun. 102 206-214 (1981). I.S. FULCHER, R. MATSAS, A.J. TURNER and A.J. KENNY, Biochem. J. 203 519-522 (1982). R.S. RUSH, M. MITAS, J.C. POWERS, T. TANAKA and L.B. HERSH, Arch. Biochem. Biophys. 231390-399 (1984). J. GAFFORD, R.A. SKIDGEL, E. ERDOS and L.B. HERSH, Biochemistry 2__22 3265-3271 (1983). R. MATSAS, I.S. FULCHER, A.J. KENNY and A.J. TURNER, Proc. Natl. Acad. Sci. USA 803111-3115 (1983). L.B. HERSH, J. Neurochem. 43487-493 (1984). C. LLORENS and J.-C. SCHWARTZ, Eur. J. Pharmacol. 69113-116 (1981). N.S. GEE, M.A. BOWES, P. BUCK and A.J. KENNY, Biochem. J. 228119-126
(1985). 17.
S. DE LA BAUME, C.C. YI, J.-C. SCHWARTZ, P. CHAILLET, MARCAIS-CALLADO and J. CONSTENTIN, Neurosci. 8 143-151 (1983).
H.
Pergamon Press
MINIREVIEW
NOMENCLATURE FOR ENKEPHALIN DEGRADING PEPTIDASES Louis B. Hersh Department of Biochemistry University Of Texas Health Science Center Dallas, Texas 75235
Summary The use of trivial names for enkephalin degrading peptidases such as "aminoenkephalinase" and "carboxyenkephalinase" imply a specificity and cellular localization which is not inherent in any of the peptidases implicated in the degradation of endogenous enkephalins. Rather than name these enzymes on the basis of one of their many substrates, it is proposed that they be named according to their general reaction type. Such a nomenclature has already been proposed for the enkephalin degrading endopeptidase 24.11 given the trivial name "enkephalinase". In a recent review article, Dua et al (I) proposed a system for naming enkephalin degrading peptidases. The nomenclature chosen is based on that used for the acetylcholine hydrolyzing enzymes. Acetylcholinesterase is the name given to the brain enzyme which hydrolyzes synaptically released acetylcholine, and pseudocholinesterases are those enzymes which can hydrolyze acetylcholine peripherally. The term "aminoenkephalinase" was proposed for an enzyme which cleaves enkephalins at the Tyr-Gly bond and for which enkephalins are highly specific substrates. The name "carboxyenkephalinase" was proposed for the enzyme which has previously been given the trivial name "enkephalinase" and which cleaves at the Gly-Phe bond of enkephalins. The name "carboxyendopeptidase" was derived from the incorrect classification of this enzyme as a dipeptidylcarboxypeptidase. In addition, the name "endoenkephalinase" was suggested for the dipeptidylaminopeptidase which cleaves enkephalins at the Gly-Gly bond. Lastly, the term "pseudoenkephalinase" is to be used for naming peptidases with broad substrate specificity which hydrolyze enkepb~lins as well as other peptides, which are located both centrally and peripherally. This nomenclature system, although potentially useful when referring specifically to enkephalin metabolism in brain in vivo, may in fact result in confusion rather than clarification of an already confusing nomenclature system. Using the definitions cited above, all of the enkephalin degrading peptidases described in the literature would be classified as "pseudoenkephalinases". The enzymes to be called "aminoenkephalinases" include the en~ephalln degrading aminopeptidase MII described by Hersh (2,3) and purified by Hui et al (4) as well as the aminopeptidase commonly referred to aminopeptidase M (5). Although both of these enzymes have been implicated in the degradation of endogenously released enkephalins in brain, neither 0024-3205/86 $3.00 + .00 Copyright (c) 1986 Pergamon Press Ltd.
1152
Naming Enkephalin Degrading Peptidases
Vol. 38, No. 13, 1986
preferentially utilizes the enkephalins as substrates. The aminopeptidase we designated as aminopeptidase MII has been shown to exhibit a broad specificity with regards to synthetic amino acid beta-naphthylamide substrates (3). In addition the enzyme also utilizes several naturally occurring peptides as substrates including alpha and beta-neo-endorphin (6), alpha and gasm~a-endorphin (2), and probably dynorphin-8 (7). In fact, it has yet to be established that this aminopeptidase is a brain specific peptidase. Aminopeptidase M, which has recently been suggested to be the major enkephalin degrading aminepeptidase in brain (5), is known to have both a broad substrate specificity and a wide tissue distribution (8). Thus, there is no definitive evidence that the aminopeptidase we have named MII acts solely as an enkephalinase in brain, and clearly aminopeptidase M does not fulfill this role. The enzyme to be given the name "carboxyenkephalinase", although initially referred to as a "dipeptidylcarboxypeptidase", has been shown to be a neutral metalloendopeptidase with a specificity for cleavage on the amino side of hydrophobic amino acids (9-11). This enzyme is similar in many respects to a group of bacterial neutral endopeptidases of which thermolysin is the best characterized. The enzyme hydrolyzes a variety of biologically active peptides including angiotensins I and II (12) , neurotensin (9), substance P (13), bradykinin (9), beta lipotropin 61-69 (14), and g ~ m a - e n d o r p h i n (14). In addition, this enzyme exhibits a wide tissue distribution, with brain tissue having a relative low content of the enzyme (15,16). Thus, although this endopeptidase appears to function in the degradation of endogenously released enkephalins in brain (17), it also lacks both the substrate specificity and tissue specificity to be called ~n enkephalinase in the same context as the name acetylcholinesterase is applied. Enzymes are generally classified according to the reaction they catalyze. In the case of peptidases with a rather broad substrate specificity the naming of an enzyme on the basis of a particular peptide substrate can only lead to confusion. For example, assume researchers studying enkephalin degradation use the name "enkephalinase" for the neutral metalloendopeptidase which belongs to the 24.11 classification of endopeptidases. Other researchers studying bradykinin metabolism find the same enzyme and name it "bradykininase", while other groups studying angiotensin I metabolism would name the enzyme "angiotensinase". A vast amount of duplication of publications could occur, and probably already has occurred, due to the variety of names adopted for the same protein. At the present time there is no definitive nomenclature adopted for the enkephalin degrading peptidases. The name "endopeptidase 24.11" proposed by Matsas et al (13) appears to be the most appropriate name for the enkephalin degrading metallo-endopeptidase commonly referred to as "enkephalinase". Similarly the enkephalin degrading aminopeptidase should probably be referred to as aminopeptidase 3.4.11 until it has been fully characterized. The use of these less descriptive terms should help to alleviate the problems encountered when enzymes of a relatively broad substrate specificity are named on the basis of only one of their substrates. On the other hand reference to an enzyme such as endopeptidase 24.11 acting as an "enkephalinase" in vivo would be appropriate provided the proper name of the enzyme were utilized.
Vol. 38, No. 13, 1986
Naming Enkephalln Degrading Peptidases
1153
Acknowledgements T h i s study was supported in part by Grant No. DA02243 from NIDA and Grant No. 1391 from the Welch Foundation, Houston, Texas.
References i. 2. 3. 4. 5. 6. 7. 8. 9. 10. II. 12. 13. 14. 15. 16.
A.K.DUA, C. PINSKY and F.S. LABELLA, Life Sci. 37985-992 (1985). L.B. HERSH, Biochemistry 202345-2350 (1981). L.B. HERSH, J. Neurochem. 441427-1435 (1985). K.-S. HUI, M. HUI and A. LAJTHA, Biochemistry 221062-1067 (1983). C. GROS, B. GIROS and J.-L. SCHWARTZ, Biochemistry 2_~4 2179-2185 (1985). C. ULRICH and L. B. HERSH, Peptides 6 4 7 5 - 4 8 2 (1985). M.G.C. GILLAN, L.E. ROBSON, A.T. MCKNIGHT and H.W. KOSTERLITZ, J. Neurochem. 451034-1042 (1985). F.E. PALMIERI, J.J. PETRELLI and P.E. WARD, Biochem. Parmacol. 34 2309-2317 (1985). J. ALMENOFF, S. WILK and M. ORLOWSKI, Biochem. Biophys. Res. Commun. 102 206-214 (1981). I.S. FULCHER, R. MATSAS, A.J. TURNER and A.J. KENNY, Biochem. J. 203 519-522 (1982). R.S. RUSH, M. MITAS, J.C. POWERS, T. TANAKA and L.B. HERSH, Arch. Biochem. Biophys. 231390-399 (1984). J. GAFFORD, R.A. SKIDGEL, E. ERDOS and L.B. HERSH, Biochemistry 2__22 3265-3271 (1983). R. MATSAS, I.S. FULCHER, A.J. KENNY and A.J. TURNER, Proc. Natl. Acad. Sci. USA 803111-3115 (1983). L.B. HERSH, J. Neurochem. 43487-493 (1984). C. LLORENS and J.-C. SCHWARTZ, Eur. J. Pharmacol. 69113-116 (1981). N.S. GEE, M.A. BOWES, P. BUCK and A.J. KENNY, Biochem. J. 228119-126
(1985). 17.
S. DE LA BAUME, C.C. YI, J.-C. SCHWARTZ, P. CHAILLET, MARCAIS-CALLADO and J. CONSTENTIN, Neurosci. 8 143-151 (1983).
H.