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Primary Hyperoxaluria Type 1: AGT Mistargeting Highlights the Fundamental Differences Between the Peroxisomal and Mitochondrial Protein Import Pathways

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Primary Hyperoxaluria Type 1: AGT Mistargeting Highlights the Fundamental Differences Between the Peroxisomal and Mitochondrial Protein Import Pathways CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1763 (2006) 1776–1784 www.elsevier.com/locate/bbamcr Review Primary hyperoxaluria type 1: AGT mistargeting highlights the fundamental differences between the peroxisomal and mitochondrial protein import pathways Christopher J. Danpure Department of Biology, University College London, Gower Street, London WC1E 6BT, UK Received 28 April 2006; received in revised form 1 August 2006; accepted 18 August 2006 Available online 24 August 2006 Abstract Primary hyperoxaluria type 1 (PH1) is an atypical peroxisomal disorder, as befits a deficiency of alanine:glyoxylate aminotransferase (AGT), which is itself an atypical peroxisomal enzyme. PH1 is characterized by excessive synthesis and excretion of the metabolic end-product oxalate and the progressive accumulation of insoluble calcium oxalate in the kidney and urinary tract. Disease in many patients is caused by a unique protein trafficking defect in which AGT is mistargeted from peroxisomes to mitochondria, where it is metabolically ineffectual, despite remaining catalytically active. Although the peroxisomal import of human AGT is dependent upon the PTS1 import receptor PEX5p, its PTS1 is exquisitely specific for mammalian AGT, suggesting the presence of additional peroxisomal targeting information elsewhere in the AGT molecule. This and many other functional peculiarities of AGT are probably a consequence of its rather chequered evolutionary history, during which much of its time has been spent being a mitochondrial, rather than a peroxisomal, enzyme. Analysis of the molecular basis of AGT mistargeting in PH1 has thrown into sharp relief some of the fundamental differences between the requirements of the peroxisomal and mitochondrial protein import pathways, particularly the properties of peroxisomal and mitochondrial matrix targeting sequences and the different conformational limitations placed upon importable cargos. © 2006 Elsevier B.V. All rights reserved. Keywords: Alanine:glyoxylate aminotransferase; Kidney stone; Mitochondrial protein trafficking; Oxalate metabolism; Peroxisomal protein trafficking; Primary hyperoxaluria type 1 1. PH1 and AGT deficiency deposition of insoluble calcium oxalate (CaOx) in the kidney and urinary tract, as various combinations of nephrocalcinosis Primary hyperoxaluria type 1 (PH1, MIM 259900) is a rare (diffuse deposition throughout the renal parenchyma) and/or autosomal recessive disorder of metabolism caused by a urolithiasis (calculi or stones). This eventually leads to renal functional deficiency of the liver-specific, pyridoxal-phos- failure, following which the combined effects of increased phate-dependent enzyme alanine:glyoxylate aminotransferase oxalate synthesis and failure to remove it from the body results in (AGT, EC 2.6.1.44) [1]. In the peroxisomes of normal human the deposition of CaOx almost anywhere. The clinical hepatocytes, AGT catalyses the transamination of the interme- presentation of PH1 is heterogeneous, for example with respect diary metabolite, glyoxylate, to glycine. This can be considered to age of first symptom, levels of urinary oxalate and glycolate to be a detoxification reaction because its dysfunction in PH1 excretion, relative contributions of nephrocalcinosis and uro- allows glyoxylate to escape from the peroxisomes into the lithiasis, and rate of progression of renal pathology. cytosol where it is oxidised to oxalate, catalysed by lactate dehydrogenase, and reduced to glycolate, catalysed by glyox- 2. Relationship between genotype and enzyme phenotype ylate/hydroxypyruvate reductase (Fig. 1) [2,3]. In humans, at least, oxalate cannot be further metabolised and its increased 2.1. The structure of normal AGT synthesis and urinary excretion leads to the progressive Human AGT is a homodimeric protein, each subunit being E-mail address: [email protected]. composed of 392 amino acids with a molecular mass of about 0167-4889/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.bbamcr.2006.08.021 C.J. Danpure / Biochimica et Biophysica Acta 1763 (2006) 1776–1784 1777 Fig. 1. Metabolic consequences of peroxisomal AGT deficiency in PH1. AGT, alanine:glyoxylate aminotransferase; DAO, D-amino acid oxidase; GO, glycolate oxidase; GRHPR, glyoxylate/hydroxypyruvate reductase; LDH, lactate dehydrogenase. Solid arrows, metabolic conversions; dotted arrows, membrane or other transport. 43 kDa [4]. Its recently-described crystal structure [5] (PDB formed,itisbelievedtoplayasignificantroleinthe 1H0C) (Fig. 2) shows that each subunit can be subdivided into dimerization process per se [5]. Dimerization of AGT is very three recognizable structural/functional domains. The first 20 or important, not only because monomeric AGT has vastly so residues make up an N-terminal extension that wraps over the reduced catalytic activity [8], but also because it is unstable surface of the other subunit. The next 260 or so residues form leading to aggregation and rapid degradation [9]. Knowledge of the ‘large domain’ that contains most of the active site and the the crystal structure of AGT has provided insights into the dimerization interface. The final C-terminal ‘small domain’ processes of AGT folding, dimerization and catalytic activity, as consists of about 110 residues, which contains among other well as allowing rationalisation of the effects mutations and things the principal and ancillary peroxisomal targeting polymorphisms on these processes (see below). information [6,7] (see below). Each subunit binds one pyridoxal phosphate, which forms a Schiff base with Lys209. The large 2.2. Enzyme phenotypes in PH1 surface area of the dimerization interface explains the high stability of the AGT dimer. Although the inter-subunit The clinical heterogeneity of PH1 is matched, or possibly interaction mediated by the N-terminal extension is unlikely even exceeded, by its enzymatic heterogeneity. Three overt to make any major contribution to stability to the dimer once categories can be identified:-deficiency of AGTcatalytic activity Fig. 2. Crystal structure of human AGT. The two identical subunits are mainly coloured yellow, except for the N-terminal extensions (red) and the PTS1As (green). NH2, amino termini; KKL, carboxy-terminal PTS1s. The location of the cofactor pyridoxal phosphate is indicated (PLP in orange), as are the locations of the Pro11Leu polymorphism (11 in pink), and the mutations discussed in the text (41, 82, 170, 244 in blue). It is the N-terminal extension (red) that acts as a MTS in the presence of the Pro11Leu polymorphism. 1778 C.J. Danpure / Biochimica et Biophysica Acta 1763 (2006) 1776–1784 but not AGT immunoreactivity, deficiency of both catalytic [17]. Some of the most common co-segregate and functionally activity and immunoreactivity, and deficiency of neither interact with the common Pro11Leu polymorphism of the minor catalytic activity nor immunoreactivity. Patients in the latter allele. Many of the better-studied mutations, or mutation– category can have AGT levels up to half the mean normal level, polymorphism combinations, are associated with specific which is well within the normal range and greater than found in enzyme phenotypes, such as loss of AGT catalytic activity, many asymptomatic carriers [2]. Intermediate categories also AGT aggregation, accelerated AGT degradation, and peroxi- exist, in which patients have markedly reduced, but still some-to-mitochondrion AGT mistargeting. The most exten- detectable levels of catalytic activity and/or immunoreactivity. sively studied genotype–enzyme phenotype relationships are More detailed analysis shows the presence of two enzyme described in more detail below. phenotypes unique to PH1. In a small group of patients with almost no AGT catalytic activity and markedly reduced AGT 2.4.1. Gly82Glu immunoreactivity, AGT appears to have aggregated into intra- The Gly82Glu mutation is associated with complete loss of peroxisomal ‘cores’ [9]. In another, much larger, group of AGT catalytic activity, without any effect on enzyme stability, patients who have significant levels of AGTcatalytic activity and dimerization or targeting [18,19]. Structural analysis shows this immunoreactivity, an even more remarkable enzyme phenotype to be due to the mutant glutamate side chain filling the space is found in which AGT is mistargeted from its normal location that should be occupied by the cofactor pyridoxal phosphate [5]. in the peroxisomes to the mitochondria [10]. Although This prevents Shiff base formation with the ε-amino group of mistargeted AGT remains catalytically active, it appears to be Lys209, thereby abolishing catalytic activity [8]. Despite lack of metabolically inefficient. This is because efficient glyoxylate enzyme activity, patients homozygous for Gly82Glu have detoxification must occur at its site of synthesis (i.e. in the completely normal levels of normally compartmentalised peroxisomes), thus preventing its oxidation to oxalate, catalysed immunoreactive AGT protein. Unlike many of the missense by cytosolic LDH. Such organelle-to-organelle mistargeting, in mutations in PH1, the Gly82Glu replacement is always found which both the normal and abnormal compartments require the on the background of the major AGXT allele. protein to contain specific, yet different, targeting information, is without parallel in human genetic disease. 2.4.2. Gly41Arg The Gly41Arg mutation has been found on the background 2.3. The
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