Biosynthesis and processing of myeloperoxidase--a marker for myeloid cell differentiation.
Myeloperoxidase (MPO), a heme protein, is a major component of azurophilic granules of neutrophils. Optimal oxygen-dependent microbicidal activity depends on MPO as the critical enzyme for the generation of hypochlorous acid and other toxic oxygen products. MPO is synthesized during the promyelocytic stage of myeloid differentiation, the stage at which azurophilic granules are formed. Like other lysosomal enzymes, MPO is synthesized as a larger precursor which is subsequently processed and transported intracellularly to the lysosomes. The primary translation product is a single 80-kDa protein which undergoes cotranslational N-linked glycosylation to produce a 92-kDa glycoprotein. Glucosidases in the endoplasmic reticulum or early cis Golgi convert the proMPO to a 90-kDa form which is sorted into a prelysosomal compartment that undergoes final proteolytic maturation to native MPO, a pair of heavy-light protomers with subunits of 60 kDa and a 12 kDa. These events contrast with similar processes seen with other lysosomal enzymes in two ways. First, alkalinization of lysosomes with NH4+ does not alter processing or transport, in contrast to the pH dependence of these processes for other lysosomal enzymes. However, some studies indicate retardation of processing in the presence of the proton ionophore monensin. Second, intracellular transport of MPO is not apparently mediated by the mannose-6-phosphate receptor system. The gene for MPO is on the long arm of chromosome 17 (17q22, 23) near the breakpoint of the 15, 17 translocation of acute promyelocytic leukemia. The gene spans approximately 14 kb and contains 11 irons and 12 exons. The cloned full-length cDNA is approximately 2.2 kb and both normal bone marrow and cultured promyelocytic leukemia cells express two species of mRNA. Inherited MPO deficiency, a relatively common disorder, is associated with the absence of mature MPO but the presence of proMPO, consistent with a post-translational defect. Studies at the molecular level aimed at identifying the underlying genetic defect are thus far consistent with that hypothesis. In addition, the basis for the observed association between acquired MPO deficiency and some myeloid leukemias can now be studied at the molecular level using these probes.
Nauseef
W M
WM
Department of Medicine, VA Medical Center, Iowa City, IA.
Olsson
I
I
Arnljots
K
K
D001692:Biological Transport; D001853:Bone Marrow / Q000201:enzymology; D001854:Bone Marrow Cells; D002454:Cell Differentiation; D055598:Chemical Phenomena; D002621:Chemistry; D003594:Cytoplasmic Granules / Q000502:physiology; D005796:Genes; D006801:Humans; D007425:Intracellular Membranes / Q000201:enzymology; D009195:Peroxidase / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D009195:Peroxidase