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Maple Syrup Urine Disease MSUD Maple Syrup Urine Disease is a genetic disease in which the amino acids leucine, isoleucine and valine cannot be broken down by branched-chain alpha-keto acid dehydrogenase. http://www.msud-support.org/overv.htm http://www.newbornscreening.info/tools/GraphicsLib/MSUD.jpg General Information Introns: 8 Size of mRNA: 1781 bp Size of Protein: 445 aa Location: 19q13.1-13.2 Domains: 4 http://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi Domains E1_dh, Dehydrogenase E1 component Transketolase_N, Transketolase AcoA, Pyruvate/2-oxoglutarate dehydrogenase complex TktA, Transketolase http://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi Genes and Protein 4 Genes that could be possibly mutated: BCKDHA * BCKDHB DBT DLD Protein affected: branched-chain alpha-keto acid dehydrogenase (BCKD) Structure http://ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?db=t&form=6&dopt=s&uid=12936 Types of MSUD Classical: little or no enzyme activity <2% Intermediate: more enzyme activity 3-8% Can tolerate greater amount of leucine Intermittent: even more enzyme activity 815% Thiamine-responsive: thiamine to increase enzyme activity http://www.msud-support.org/overv.htm Mutations 4 mutations in the BCKDHA gene that can result in MSUD Classic: Tyrosine to Asparagine at aa 394 Classic: 8bp deletion from nucleotide 887-894 Intermediate: Glycine to Arginine at aa 245 Intermediate: Phenylalanine to Cysteine at aa 364 http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608348 Results of Mutations in BCKDHA Cannot breakdown amino acids leucine, isoleucine, and valine Build up to toxic levels Nervous system degeneration Can lead to encephalopathy About MSUD Recessive genetic disease – meaning that both parents must carry a mutation for the disease. Each person has two genes that code for enzyme activity. If only one gene is mutated, then the person is just a carrier of MSUD. If parents are both carriers, 1 in 4 chance that baby has MSUD 2 in 4 chance that baby will be carrier 1 in 4 chance that baby will not have mutation Characteristic Symptoms Symptoms occur in newborns within the first four to seven days of birth. Infants with this disease have poor feeding habits. Vomiting Infants show poor weight gain due to improper feeding. Increased lethargy – deep sleep, sluggish Sweet smell to urine is the major characteristic symptom for this disease. Muscle spasms and seizures Could lead to death if not treated, but is manageable. http://rarediseases.about.com/od/rarediseases1/a/062004.htm Diagnosis/ Screening Mandatory State Screening Programs Some states don’t include this test in newborn screenings Some infants are only tested after symptoms occur Blood Tests to look at amino acid levels Treatment Restrict their diet to foods without leucine, isoleucine, and valine Must continue throughout life or symptoms will reoccur During times of metabolic decompensation, patients can be treated with intra-venous hyperalimentation. Supplements can be taken so that patients receive those essential amino acids. Hypothesis MSUD is only a mammalian disease. Based on the principle that urination in mammals is different than many other species. Evidence Against Hypothesis Some of the organisms that showed up in the BLAST search: Saccharomyces cerevisiae (yeast) ... 129 3 hits [ascomycetes] Danio rerio (zebra fish) --- 680 3 hits [bony fishes] Gallus gallus (chickens) --- 714 1 hit [birds] http://www.ncbi.nih.gov/BLAST/Blast.cgi?CMD=Get&RID=1145026779-912417383991185.BLASTQ4&FORMAT_OBJECT=TaxBlast&NCBI_GI=on&DESCRIPTIONS= 500&ALIGNMENTS=250&FORMAT_BLOCK_ON_RESPAGE=Top&MASK_COLOR=1& MASK_CHAR=2 Another Hypothesis While investigating our first hypothesis, we discovered that many organisms must have a mechanism to metabolize potentially harmful amino acids such as isoleucine, leucine and valine. Conserved Domains These two domains were shown to be conserved over the whole taxa. Dehydrogenase E1 component Pyruvate/2-oxoglutarate dehydrogenase complex Results Taxonomy Report Conclusion: While amino acids are essential building blocks for proteins, buildup of these amino acids can be toxic. Every living organism must have a mechanism to metabolize these amino acids.