TY - JOUR
T1 - 3-Hydroxy-3-methylglutaryl coenzyme A lyase
T2 - Targeting and processing in peroxisomes and mitochondria
AU - Ashmarina, Lyudmila I.
AU - Pshezhetsky, Alexey V.
AU - Branda, Steven S.
AU - Isaya, Grazia
AU - Mitchell, Grant A.
N1 - Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 1999/1
Y1 - 1999/1
N2 - 3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL, E.C. 4.1.3.4) has a unique dual localization in both mitochondria and peroxisomes. Mitochondrial HL (~31.0 kDa) catalyzes the last step of ketogenesis; the function of peroxisomal HL (~33.5 kDa) is unknown. On density gradient fractionation, normal human lymphoblasts contain both peroxisomal and mitochondrial HL whereas in lymphoblasts from a patient with Zellweger syndrome, in which functional peroxisomes are absent, only the mitochondrial HL isoform was present. To study the kinetics of the dual targeting of HL, we performed pulse-chase experiments in normal and Zellweger cells. Pulse-chase studies revealed a biphasic curve for processing of the HL precursor. The first phase, with a calculated half-life of ~3 h in both normal and Zellweger fibroblasts and lymphoblasts and in HepG2 cells, presumably reflects mitochondrial import and processing of the precursor; the second (t(1/2), 12- 19 h) is present only in normal cells and presumably represents the half- life of peroxisomal HL. The half-life of mature mitochondrial HL was 14 to 19 h in both normal and Zellweger cells. Studies of the HMG-CoA lyase precursor in isolated rat mitochondria showed a rate of processing ~2.6-fold lower than that of the ornithine transcarbamylase precursor.
AB - 3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL, E.C. 4.1.3.4) has a unique dual localization in both mitochondria and peroxisomes. Mitochondrial HL (~31.0 kDa) catalyzes the last step of ketogenesis; the function of peroxisomal HL (~33.5 kDa) is unknown. On density gradient fractionation, normal human lymphoblasts contain both peroxisomal and mitochondrial HL whereas in lymphoblasts from a patient with Zellweger syndrome, in which functional peroxisomes are absent, only the mitochondrial HL isoform was present. To study the kinetics of the dual targeting of HL, we performed pulse-chase experiments in normal and Zellweger cells. Pulse-chase studies revealed a biphasic curve for processing of the HL precursor. The first phase, with a calculated half-life of ~3 h in both normal and Zellweger fibroblasts and lymphoblasts and in HepG2 cells, presumably reflects mitochondrial import and processing of the precursor; the second (t(1/2), 12- 19 h) is present only in normal cells and presumably represents the half- life of peroxisomal HL. The half-life of mature mitochondrial HL was 14 to 19 h in both normal and Zellweger cells. Studies of the HMG-CoA lyase precursor in isolated rat mitochondria showed a rate of processing ~2.6-fold lower than that of the ornithine transcarbamylase precursor.
KW - Amino acid metabolism
KW - Hydroxymethylglutaryl CoA
KW - Inborn errors
KW - Ketoacid lyases
KW - Ketone bodies
KW - Mitochondria
KW - Peroxisomes
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M3 - Article
C2 - 9869651
AN - SCOPUS:0032948460
SN - 0022-2275
VL - 40
SP - 70
EP - 75
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 1
ER -