Iduronidase (EC 3.2.1.76, L-iduronidase, alpha-L-iduronidase, laronidase), sold as Aldurazyme, is an enzyme with the systematic name glycosaminoglycan alpha-L-iduronohydrolase. This enzyme catalyses the hydrolysis of unsulfated alpha-L-iduronosidic linkages in dermatan sulfate.It is a glycoprotein enzyme found in the lysosomes of cells. It is involved in the degeneration of glycosaminoglycans such as dermatan sulfate and heparan sulfate. The enzyme acts by hydrolyzing the terminal alpha-L-iduronic acid residues of these molecules, degrading them. The protein is reported as having a mass of approximately 83 kilodaltons. Pathology
A deficiency in the IDUA protein is associated with mucopolysaccharidoses (MPS). MPS, a type of lysosomal storage disease, is typed I through VII. Type I is known as Hurler syndrome and type I,S is known as Scheie syndrome, which has a milder prognosis compared to Hurlers. In this syndrome, glycosaminoglycans accumulate in the lysosomes and cause substantial disease in many different tissues of the body. IDUA mutations result in the MPS 1 phenotype, which is inherited in an autosomal recessive fashion. The defective alpha-L-iduronidase results in an accumulation of heparan and dermatan sulfate within phagocytes, endothelium, smooth muscle cells, neurons, and fibroblasts. Under electron microscopy these structures present as laminated structures called Zebra bodies. Prenatal diagnosis of this enzyme deficiency is possible. Aldurazyme
General
Aldurazyme is the name of the commercialized variant of the enzyme iduronidase, which hydrolyzes the alpha-L-iduronic acid residues of dermatan sulfate and heparin sulfate. Produced in Chinese hamster ovaries by recombinant DNA technology, Aldurazyme is the manufactured by BioMarin Pharmaceutical Inc. and distributed by Genzyme Corporation (a subsidiary of Sanofi).
Research
While many antioxidants have been researched to treat a large number of diseases by reducing the negative effect of oxidative stress, acetylcysteine is one of the few that has yielded promising results, and is currently already approved for the treatment of paracetamol overdose. In mouse mdx models of Duchennes muscular dystrophy, treatment with 1–2% acetylcysteine in drinking water significantly reduces muscle damage and improves strength. It is being studied in conditions such as autism, where cysteine and related sulfur amino acids may be depleted due to multifactorial dysfunction of methylation pathways involved in methionine catabolism. Animal studies have also demonstrated its efficacy in reducing the damage associated with moderate traumatic brain or spinal injury, and also ischaemia-induced brain injury. In particular, it has been demonstrated to reduce neuronal losses and to improve cognitive and neurological outcomes associated with these traumatic events. It has been suggested that acetylcysteine may help people with Samters triad by increasing levels of glutathione allowing faster breakdown of salicylates, although there is no evidence that it is of benefit. Small studies have shown acetylcysteine to be of benefit to people with blepharitis. It has been shown to reduce ocular soreness caused by Sjögrens syndrome. It has been shown that N-acetylcysteine may protect the human cochlea from subclinical hearing loss caused by loud noises such as impulse noise. In animal models, it reduced age-related hearing loss. It has been shown effective in the treatment of Unverricht-Lundborg disease in an open trial in four patients.