Huma Naz, Faizan Ahmad, Md. Imtaiyaz Hassan
Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.


Lysosomal storage diseases are occurs due to inherited deficiencies in various enzymes involved in basic metabolic processes. These enzymes are Cathepsines, Aspartylglucosa-minidase, Hexosaminidase, β-glucuronidase, α-L-iduronidase, α-glucosidase, Arylsulfatase A & B, Myeloperoxidase, Acid phosphatise, and DNAse. All these enzymes are involved in the degradation of respective metabolites and their deficiency leads to the lysosomal storage diseases. Interestingly, all these enzymes share several common features despite of their structural differences. The transport of these enzymes to the lysosomes from their site of synthesis (rough endoplasmic reticulum) is mediated by a series of protein and carbohydrate recognition signals present on the enzymes sequence or structure. Their transport depends on the degree of glycosyaltion and recognition of elements present in the three-dimensional structure of enzyme by phosphotransferase. Structure analysis suggests that most of these enzymes possess phophotransferase recognition site and lysosomal targeting motif, which are essential for the targeting and successful delivery of these enzymes to the lysososmes. In cathepsin D the β-hairpin motif formed by residues Asn70 and Asn199 and the N-linked glycan chains were found to be important for targeting of cathepsin D to lysosome. Similarly, all these lysosomal enzymes have their different lysosomal targeting motif and they share both sequence and structural similarity considerably. Likewise, the residues from 179 to 201 of β-glucronidase were predicted to be involved in the lysosomal targeting. Furthermore, site-directed mutagenesis studies suggested that phosphotransferase recognition may not involve a universal β-hairpin motif but be based on small contact points offered by lysine residues and all these enzymes have conserved lysine residues which were proposed to be essential for the phosphotransferase recognition. An accurate structure data for these enzymatic proteins should helpful in better understanding the molecular basis of lysosomal storage diseases and their treatment. Read More …

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