maple syrup urine disease blocked pathway of bcaa catabolism
Post on 30-Dec-2015
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Its being proposed that therapy with phenyl butyrate in MSUD patients has been associated with a selective reduction in branched-chain amino acids (BCAA) in spite of adequate dietary protein intake.
Hypothesis
RATS (Rattus norvegicus)
Age (10-30 days old) The physiology is easier to
monitor in the rat The physiology is more
like the corresponding human condition
The distance effects of drug administration to specific anatomical areas
Over time, a volume of data has developed that will take years to be replicated in the mouse .
RESEARCH SUBJECTS
E1: 2-oxoisovalerate dehydrogenase, composed itself of two polypeptide chains:
E1-alpha (probably the catalytic subunit) and E1-beta; E1 IS THE MOST COMMON SITE OF
MUTATIONS. E2: dihydrolipoamide acyltransferase. E3: dihydrolipoamide dehydrogenase.
BCKDH
Specific Aim: To increase the proportion of active BCKDH.In order to see how phenyl butyrate increases the activity of BCKDH enzyme, the following procedure will be followed;
In vitro testing with fibroblast cells from rat In vivo testing with rats In vivo testing with human subjects
RESEARCH DESIGN
In vitro Test (Fibroblast)
Four Rats : 2 healthy control , 2 MSUD patients
2 induced with MSUD via BCAA IV administration
Fibroblast cells are collected from subjects 2mm phenyl
butyrate CIC
Based on the success of the in vitro test, a similar test is carried out in humans and the serum levels of BCAA and BCKA data before and after administration of phenyl butyrate generates charts for comparison.
In vivo testing with Human Subjects
PROPOSED MECHANISM
α –keto isovalerate+ CIC + BKD+ Phenyl butyrate +NAD+ + TPP RCOCoA+CO2+NADH+
+ + BKD + + +
+ CO2 +
Team A rats are orally given a saline solution for three days
Team B rats are orally given phenyl butyrate for three days .
After 3 days they are sacrificed, livers harvested and analysed using western blot
In vivo with Rats
Results
It contains Na+ hence, patients on salt diet cannot use
It can cause drowsiness It contains inactive ingredients that may
cause allergic reactions
Side Effects of Phenyl butyrate
INNOVATION: Lactating Porcine Mammary Tissue Catabolizes
Branched-Chain Amino Acids for Glutamine and Aspartate Synthesis
Future Directions
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2675817/
http://ars.els-cdn.com/content/image/1-s2.0-S0014299901014893-gr6.jpg
http://wildpro.twycrosszoo.org/S/0MRodenti/muridae/rattus/Rattus_norvegicus/Rattus_norvegicus.htm
Sources
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