1978
DOI: 10.1128/jb.134.2.506-513.1978
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Carboxypeptidase displaying differential velocity in hydrolysis of methotrexate, 5-methyltetrahydrofolic acid, and leucovorin

Abstract: An enzyme that catalyzes the hydrolysis of folic acid and the antifolate methotrexate nearly 20 times more rapidly than the hydrolysis of 5-methyltetrahydrofolate was extracted from a gram-negative bacterium tentatively identified as a Flavobacterium sp. The enzyme was purified 500-fold and found to have a molecular weight of about 53,000. Apparently a metallo-enzyme, it is inhibited by citrate and ethylenediaminetetraacetic acid (EDTA). Ca2+, Co2+, Mg2+, and Zn2+ reverse inhibition by EDTA, whereas Ca2+ and Z… Show more

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Cited by 31 publications
(8 citation statements)
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“…The carboxypeptidase-G class of enzymes hydrolyze the terminal glutamate from naturally occurring folates and folate analogs, such as MTX [60]. Carboxypeptidase-G rapidly converts MTX to the inactive metabolites DAMPA and glutamic acid, thus providing an alternate route of elimination to renal excretion.…”
Section: Investigational Treatment Approachesmentioning
confidence: 99%
“…The carboxypeptidase-G class of enzymes hydrolyze the terminal glutamate from naturally occurring folates and folate analogs, such as MTX [60]. Carboxypeptidase-G rapidly converts MTX to the inactive metabolites DAMPA and glutamic acid, thus providing an alternate route of elimination to renal excretion.…”
Section: Investigational Treatment Approachesmentioning
confidence: 99%
“…Nor, with one exception, is much known about pABAGlu-hydrolyzing enzymes from other organisms. The only well-characterized protein known to hydrolyze pABAGlu 5 is carboxypeptidase G (CPG, EC 3.4.17.11), a di-zinc enzyme from Pseudomonas and other bacteria (McCullough et al, 1971;Albrecht et al, 1978;Sherwood et al, 1985). CPG also cleaves the pABA-glutamate bond in folates and folate analogs, releasing pteroate 3 and glutamate 6 fragments, and can remove the γ-glutamyl tail from polyglutamates by exopeptidase action.…”
Section: Introductionmentioning
confidence: 99%
“…3,15 High-flux hemodialysis is the most effective method of extracorporeal methotrexate removal but requires five to six daily treatments (4-6 hours per session) with a very high blood flow rate (400 ml/minute) 16 ; it often results in transient rebound increases in methotrexate concentrations and has been associated with low blood pressure, fatigue, chest pain, leg cramps, nausea, and headaches. [17][18][19] Glucarpidase, previously known as carboxypeptidase G2, is a carboxypeptidase G enzyme isolated from Pseudomonas species strain RS-16 that hydrolyzes the terminal glutamate residue from methotrexate, along with other naturally occurring folates and folate analogs, 20 and it was recently approved by the United States Food and Drug Administration (Voraxaze; BTG International, Inc., West Conshohocken, PA). The hydrolysis of methotrexate and its active metabolite 7-hydroxymethotrexate by glucarpidase forms the inactive metabolites glutamate, 2,4-diamino-N 10methylpteroic acid (DAMPA), 21 and (OH)-DAMPA, which are partially metabolized by the liver.…”
mentioning
confidence: 99%
“…Glucarpidase, previously known as carboxypeptidase G2, is a carboxypeptidase G enzyme isolated from Pseudomonas species strain RS‐16 that hydrolyzes the terminal glutamate residue from methotrexate, along with other naturally occurring folates and folate analogs, and it was recently approved by the United States Food and Drug Administration (Voraxaze; BTG International, Inc., West Conshohocken, PA). The hydrolysis of methotrexate and its active metabolite 7‐hydroxymethotrexate by glucarpidase forms the inactive metabolites glutamate, 2,4‐diamino‐N 10 ‐methylpteroic acid (DAMPA), and (OH)‐DAMPA, which are partially metabolized by the liver .…”
mentioning
confidence: 99%