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Molecular evolution of the intracellular targeting of alanine:glyoxylate aminotransferase

Holbrook, Joanna Dawn; (2001) Molecular evolution of the intracellular targeting of alanine:glyoxylate aminotransferase. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The subcellular distribution of the hepatic metabolic enzyme alanine:glyoxylate aminotransferase (AGT) has changed on numerous occasions throughout the evolution of mammals. The AGT distribution in the livers of these species seems to show a relationship to diet. Thus AGT tends to be mitochondrial in carnivores, peroxisomal in herbivores and both mitochondrial and peroxisomal in omnivores. The archetypal mammalian AGT gene has the potential to encode an N-terminal mitchondrial targeting sequence (MTS) and a C-terminal peroxisomal targeting sequence type 1 (PTS1). The variable subcellular distribution of AGT results from the variable use of two alternative transcription and translation start sites which include or exclude the MTS from the open reading frame (ORF). The functionality and evolution of the targeting sequences of AGT are extraordinary. The MTS of AGT is often excluded from the ORF and the PTS1 is protein context dependent. This study further investigates the following: 1. The molecular mechanism for the variable distribution of AGT in different species 2. The selective pressure that acts on the targeting of AGT to cause its variable localization. The results presented in this thesis show the following: The molecular explanation for the unusual mitochondrial and cytosolic distribution of amphibian AGT was determined, using the xenopus as a representative species. It is the first AGT gene studied, which does not encode a peroxisomal targeting sequence. Xenopus AGT has the potential to encode two RNA transcripts. One of these includes the MTS and the other has no targeting information. Two novel molecular mechanisms for a solely peroxisomal distribution of AGT were suggested for certain primate species. These were the loss of a transcription start site excluding the MTS from the RNA transcript, and accumulation of mutations in the MTS that are incompatible with its function. The context specificity of PTS1s, in general, was explored by undertaking an extensive literature survey of C-terminal tripeptides that have some characteristics of PTS1s. This information was related to the peroxisomal targeting of AGT. Analysis of the relative number of synonymous and nonsynonymous mutations accumulated in the region of primate AGT genes, encoding the MTS, suggested that there has been recent strong, yet episodic, positive selection pressure to lose, or diminish, mitochondrial AGT targeting in anthropoid primates. The selection pressure is possibly connected to diet. Non-mammalian AGT homologues were identified from sequence databases. These, along with the xenopus AGT data, suggested a new hypothesis for the ancestral distribution of AGT. Stronger evidence for the theory of diet as the selective pressure driving the evolution of AGT subcellular targeting was acquired by comparative analysis of the distribution of AGT and diet, which showed a significant correlation.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Molecular evolution of the intracellular targeting of alanine:glyoxylate aminotransferase
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Pure sciences; Alanine:glyoxylate aminotransferase
URI: https://discovery.ucl.ac.uk/id/eprint/10097287
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