RT Book, Section
A1 Vockley, Jerry
A2 Kline, Mark W.
SR Print(0)
ID 1182928992
T1 Disorders of Ketolysis
T2 Rudolph's Pediatrics, 23e
YR 2018
FD 2018
PB McGraw-Hill Education
PP New York, NY
SN 9781259588594
LK accesspediatrics.mhmedical.com/content.aspx?aid=1182928992
RD 2024/04/24
AB Ketolysis  involves  esterification  of  acetylacetate  (AcAc)  to  AcAc-coenzyme  A  (CoA)  by  succinyl-CoA:3-oxoacid  transferase  (SCOT,  OXCT1  gene)  and  hydrolysis  of  AcAcCoA  by  mitochondrial  acetoacetyl-CoA  thiolase  (T2,  ACAT1  gene)  to  form  acetyl-CoA.  Inherited  disorders  of  ketolysis  involve  these  2  enzymes  and  cause  persistent  or  episodic  ketoacidosis.  If  SCOT  is  entirely  lacking,  ketolysis  is  completely  blocked,  but  if  functional  T2  is  completely  absent,  some  ketolysis  is  still  possible,  likely  due  to  the  presence  of  another  mitochondrial  enzyme,  medium  chain  3-ketoacyl-CoA  thiolase,  that  has  some  activity  for  hydrolyzing  AcAcCoA.  This  latter  enzyme  may  explain  in  part  why  permanent  ketosis  is  often  observed  in  SCOT  deficiency  but  not  in  T2  deficiency.  Ketone  body  production  is  regulated  by  the  hormones  glucagon  and  catecholamines,  which  induce  free  fatty  acid  (FFA)  mobilization  from  adipose  tissue,  fatty  acid  oxidation,  and  ketogenesis  in  the  liver,  while  insulin  suppresses  these  steps.  Ketogenic  stresses  including  fasting,  prolonged  exertion,  febrile  illnesses,  and  vomiting  and  diarrhea,  leading  to  both  FFA  oxidation  and  ketone  body  synthesis.  The  enzymes  of  ketogenesis  (see  Chapter  146);  hydroxymethylglutaryl-CoA  synthase  and  lyase,  generate  AcAc,  which  is  then  reduced  by  mitochondrial  D-β-hydroxybutyrate  (D-βOHB)-dehydrogenase  (BDH1)  in  the  liver  to  D-βOHB.  Ketone  bodies  then  circulate  to  peripheral  tissues,  where  BDH1  regenerates  AcAc,  allowing  SCOT  and  T2  to  generate  acetyl-CoA  in  order  to  maintain  cellular  energy  production  via  the  tricarboxylic  acid  (TCA)  cycle  and  spare  glucose  utilization.