Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In eukaryotic cells, lysosomes represent a major site for macromolecule degradation. Hydrolysis products are eventually exported from this acidic organelle into the cytosol through specific transporters. Impairment of this process at either the hydrolysis or the efflux step is responsible of several lysosomal storage diseases. However, most lysosomal transporters, although biochemically characterized, remain unknown at the molecular level. In this study, we report the molecular and functional characterization of a lysosomal amino acid transporter (LYAAT-1), remotely related to a family of H+-coupled plasma membrane and synaptic vesicle amino acid transporters. LYAAT-1 is expressed in most rat tissues, with highest levels in the brain where it is present in neurons. Upon overexpression in COS-7 cells, the recombinant protein mediates the accumulation of neutral amino acids, such as gamma-aminobutyric acid, l-alanine, and l-proline, through an H+/amino acid symport. Confocal microscopy on brain sections revealed that this transporter colocalizes with cathepsin D, an established lysosomal marker. LYAAT-1 thus appears as a lysosomal transporter that actively exports neutral amino acids from lysosomes by chemiosmotic coupling to the H+-ATPase of these organelles. Homology searching in eukaryotic genomes suggests that LYAAT-1 defines a subgroup of lysosomal transporters in the amino acid/auxin permease family.
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PMID:Identification and characterization of a lysosomal transporter for small neutral amino acids. 1139 Sep 72

A first mammalian lysosomal transporter (LYAAT-1) was recently identified and functionally characterized. Preliminary immunocytochemical data revealed that LYAAT-1 localizes to lysosomes in some neurons. In order to determine whether it is expressed in specific neuron populations and other cell types, and to confirm whether it is localized at the membrane of lysosomes, we used in situ hybridization and immunohistochemistry methods in adult rat central nervous system (CNS). We found that LYAAT-1 is expressed in most areas of the CNS, specifically in neurons, but also in choroid plexus and ependymal epithelium cells. LYAAT-1-IR (immunoreactivity) levels varied among different neuroanatomical structures but were present in neurons independently of the neurotransmitter used (glutamate, GABA, acetylcholine, noradrenaline, serotonin, or glycine). Light and confocal microscopy demonstrated that LYAAT-1 and the lysosomal marker cathepsin D colocalized throughout the brain and electron microscopy showed that LYAAT-1-IR was associated with lysosomal membranes. In addition, LYAAT-1-IR was also found associated with other membranes belonging to the Golgi apparatus and lateral saccules and less frequently with multivesicular bodies, endoplasmic reticulum, and occasionally with the plasma membrane. The localization of LYAAT-1 at the lysosomal membrane is consistent with the view that it mediates amino acid efflux from lysosomes. Furthermore, its cell expression pattern suggests that it may contribute to specialized cellular function in the rat CNS such as neuronal metabolism, neurotransmission, and control of brain amino acid homeostasis.
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PMID:Lysosomal amino acid transporter LYAAT-1 in the rat central nervous system: an in situ hybridization and immunohistochemical study. 1276 25