University of PennsylvaniaBIOL 204BIOL 204 (2017) Problem Set 6 + Key

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Biology  204 Spring  2017/REA/ELLIOTT 1 Problem  Set  6:  β-­‐oxidation  and  oxidative  phosphorylation Questions: Note that the questions in blue font will n... ot be graded but have instead been incorporated into this problem set to help you prepare for the final exam. As noted before, it is important that you have a reasonable understanding of what is being asked in the problems and work on them before coming to the discussion. You will need to make use of your lecture notes and the course textbook (or other sources) when attempting to several of these questions, especially those demanding a more integrative approach. 1. Pyruvate  carboxylase  deficiency  is  a  rare inherited  disorder  that  causes  lactic  acid   and  other  potentially  toxic  compounds  to  reach  unusually  high  levels in  the  blood.     More  often  than  not,  this  is  accompanied  by  developmental  delay  and  failure  to   thrive  starting  in  the  neonatal  or  early  infantile  period. The  severity  of  this   autosomal  recessive  disease  ranges  from  what  is  deemed ‘type  B’,  where  the   neonatal  onset  of  neurological  symptoms  and  lactic  acidosis  lead  to  death  within   months  of  birth,  through  ‘type  A’,  where  neurological  effects  are  permanent  and   those  affected  die  in  early  childhood  but  generally  survive  infancy,  to  ‘type  C’,   where  sporadic  bouts  of  lactic  acidosis  occur  in  an  otherwise  healthy  patient. Pyruvate  carboxylase catalyzes  a  key  reaction  in  gluconeogenesis:  the  ATPdependent  carboxylation  of  pyruvate  to  oxaloacetate  (pyruvate  +  HCO3-­‐ +  ATP  ⇌ oxaloacetate  +  ADP  +  Pi). As  you  know,  this  is  an  example  of  an  anaplerotic  reaction   that  among  other  things serves  to  replenish  TCA  cycle  intermediates. A. Provide  another  example  of  an  anaplerotic  reaction  that  serves  to  replenish   TCA  cycle  intermediates  and  explain  why  anaplerotic  reactions  are  needed  if   metabolism  is  to  be  sustainable. B. Pyruvate  carboxylase  is  allosterically  activated whereas  the  pyruvate   dehydrogenase  complex  is  end-­‐product  inhibited  by  acetyl-­‐CoA.    Explain  why   is  makes  good  sense  metabolically  for  acetyl-­‐CoA  to  promote  the  activity  of   pyruvate  carboxylase when  the  pyruvate  dehydrogenase  complex  is  inhibited   by  the  same  intermediate. C. After  a  meal  rich  in  fatty  acids  and  relatively  low  in  carbohydrates,  there  is  a   significant  increase  in  the  concentration  of  acetyl-­‐CoA.    How  does  allosteric   activation of  pyruvate  carboxylase  by  acetyl-­‐CoA  serve to  inhibit  glycolysis   while  at  the  same  time  increasing the  rate  of  oxidation  of  acetyl-­‐CoA  in  the   TCA  cycle? Note  that  PFK-­‐1,  which  catalyzes  the  rate-­‐limiting  step  of   glycolysis,  is  allosterically  activated  by  ADP  and  AMP but  allosterically   inhibited  by  ATP  and  citrate. D. As  an  attending  physician  at  CHOP  you  have  several  children  in your  care  who   have a  genetic  deficiency  in  pyruvate  carboxylase.    As  a  matter  of  course,   these  children  are  treated  with  continuous  intravenous glucose  (6-­‐9   mg/kg/min)  to ensure  that  they have  a  constant  supply  of  glucose  to  minimize   the  likelihood  of hypoglycemia and/or  lactic  acidosis.   However,  in  an  attempt  Biology  204 Spring  2017/REA/ELLIOTT 2 to  further  improve  their  overall  health  and  quality  of  life,  you  augment  the   glucose  drip with  infusions  of citrate,  aspartate  and  biotin  at  doses  of  3.5   mmol/kg/day,  5  mmol/kg/day  and  30  mg/kg/day,  respectively.    Why  did  you   do  this,  and  how  do  you  think  such  supplements  might  improve  the  prognosis   for  these  children?    In  thinking  about  this,  appreciate  that  enzyme  deficiencies   are  not  true  enzyme  knockouts.    The  enzymes  in  question  are  usually  present,   albeit  at  lower  levels  or  with  lower  intrinsic  activities  than  found  in  normal   individuals. 2. A  68  kg  (150  lb)  adult  requires  a  caloric  intake  of  2,000  kcal  (8,360  kJ)  of  food  per   day  (every  24  h).    The  food  is  metabolized  and  the  free  energy  is  used  to  synthesize   ATP,  which  then  provides  energy  for  the  body’s  daily  chemical  and  mechanical   requirem [Show More]

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