Sandbox Reserved 191: Difference between revisions

Mutations  in Palmitoyl Protein Thioesterase 1 (PPT-1) can cause three types of disorders:  [http://en.wikipedia.org/wiki/Infantile_neuronal_ceroid_lipofuscinosis Infantile Neuronal Ceroid Lipofuscinosis (INCL)],  [http://www.mun.ca/biology/dmarshall/One%20Pager.htm Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL)], and [http://ghr.nlm.nih.gov/condition/juvenile-batten-disease Juvenile Neuronal Cerioid Lipofuscinosis (JNCL)]. The severity of most of the mutations are dependent upon their location inside the protein with respect to the catalytic triad. “Mutations that affect catalysis or substrate binding or disrupt proper folding of the core result in inactive enzymes and lead to a severe clinical phenotype” <ref name="mutations" />. Other mutations that cause less severe disorders can sometimes retain some residual thioesterase activity. These less severe mutations are believed to have small, local changes in areas of the protein that are far away from the catalytic <scene name='43/436866/Triad_w_zoom/2'>triad</scene> and palmitate binding site. A more detailed explanation of how some of the different disorders arise through mutations is explained below<ref name="mutations" />.  

Various mutations have been found in INCL patients<ref name="Ryan-1">PMID:10191107</ref>. Most of these mutations are caused by nonsense or missense mutations within close proximity to the catalytic triad. These mutations lead to an inactive PPT-1 enzyme as they are predicted to create unfavorable steric, polar, and electrostatic interactions that could disturb the nucleophilic elbow <ref name="mutations" />. The nucleophilic elbow is responsible for proper location and orientation of the Ser-115. The catalytic activity of PPT-1 is greatly reduced if the positioning of Ser-115 is altered, as Ser-115 must be properly orientated to be activated by His-289 to be positioned to attack the substrate. An example of a INCL mutation such as <scene name='58/580837/Methionine/6'>Val181Met</scene> and <scene name='58/580837/Lysine_mutation/3'>Glu184Lys</scene> gives a good depiction of how the increase in size in the mutated amino acids and positive charge on the inserted lysine residue would create steric and polar clashes with the adjacent helices of the binding pocket compared to the <scene name='58/580837/Val181glu184/2'>Normal Val-181 & Glu-184</scene>  <scene name='58/580837/Arginine_fine/4'>Normal Arg-122</scene> which is below <ref name="Ryan-1">PMID:10191107</ref>.