TY  - CHAP
M1  - Book, Section
TI  - Disorders of Biotin Metabolism
A1  - Zempleni, Janos
A1  - Barshop, Bruce A.
A1  - Cordonier, Elizabeth L.
A1  - Baier, Scott R.
A1  - Gertsman, Ilya
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
Y1  - 2019
N1  - 10.1036/ommbid.188
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - Biotin,  a  water-soluble  vitamin  belonging  to  the  B  complex,  acts  as  a  covalently  bound  coenzyme  in  each  of  five  carboxylases  in  humans:  pyruvate  carboxylase,  propionyl-CoA  carboxylase,  3-methylcrotonyl-CoA  carboxylase,  and  acetyl-CoA  carboxylases  1  (alpha)  and  2  (beta).  These  enzymes  have  important  roles  in  gluconeogenesis,  fatty  acid  synthesis,  mitochondrial  import  of  fatty  acids,  and  amino  acid  catabolism.  Biotin  is  derived  from  the  diet  and  possibly  also  from  the  synthetic  activity  of  gastrointestinal  microflora.Each  of  the  carboxylases  is  synthesized  as  an  inactive  apoenzyme  that  is  subsequently  biotinylated  through  two  partial  reactions,  each  of  which  is  catalyzed  by  the  enzyme  holocarboxylase  synthetase.  Acetyl-CoA  carboxylase  1  functions  principally  in  the  cytoplasm,  whereas  the  other  four  holocarboxylases  function  in  mitochondria  and  the  outer  mitochondrial  membrane.  Ultimately,  these  enzymes  are  degraded  proteolytically,  probably  by  the  lysosomal  autophagic  system.  The  biotin-containing  products  of  degradation,  biocytin  (ɛ-N-biotinyl-L-lysine)  and  biotinyl  peptides  are  acted  on  by  biotinidase,  which  cleaves  the  amide  bond  between  lysine  and  biotin.  The  liberated  biotin  is  recycled  and  enters  the  free  biotin  pool.  Biotinidase  also  has  been  shown,  in  presence  of  biocytin,  to  transfer  biotin  to  nucleophilic  acceptors,  such  as  histones.  This  function  appears  to  be  an  in  vitro  artifact  with  no  physiological  significance.There  are  two  major  defects  in  the  cycle  of  biotin  utilization  in  humans.  Both  disorders  result  in  multiple  carboxylase  deficiency.  Holocarboxylase  synthetase  deficiency  (MIM  253270),  also  known  as  early-onset  (neonatal)  multiple  carboxylase  deficiency  based  on  the  usual  age  of  onset  of  symptoms,  is  a  disorder  of  biotinylation.  Biotinidase  deficiency  (MIM  253260),  also  known  as  late-onset  (juvenile)  multiple  carboxylase  deficiency,  is  a  disorder  of  biotin  recycling.  Deficiencies  of  individual  carboxylases  are  rare.Holocarboxylase  synthetase  deficiency  has  been  described  in  <100  children.  Clinical  symptoms  include  feeding  and  breathing  difficulties,  hypotonia,  seizures,  lethargy,  sometimes  progressing  to  coma,  and  developmental  delay.  Some  children  exhibit  skin  rash  and  alopecia.  Affected  children  exhibit  metabolic  acidosis,  organic  aciduria,  and  mild  to  moderate  hyperammonemia.  The  organic  aciduria  includes  elevated  concentrations  of  β-hydroxyisovalerate,  β-methylcrotonylglycine,  β-hydroxypropionate,  methylcitrate,  lactate,  and  tiglylglycine.The  enzyme  defect  has  been  demonstrated  in  lymphocytes,  cultured  fibroblasts,  and  cultured  lymphoblasts  from  affected  children.  Holocarboxylase  synthetase  in  the  tissues  of  most  of  the  children  examined  have  increased  Km  values  for  biotin,  although  a  few  have  been  described  with  a  normal  Km  and  a  decreased  Vmax.Holocarboxylase  synthetase  deficiency  is  inherited  as  an  autosomal  recessive  trait.  Heterozygosity  cannot  be  confirmed  by  measuring  enzymatic  activity  in  the  tissues  of  parents  but  should  be  determined  by  mutation  analysis.The  normal  mammalian  enzyme  has  been  purified  and  characterized  biochemically,  and  multiple  mutations  within  the  synthetase  gene  have  been  identified.  Some  of  these  mutations  occur  within  the  biotin-binding  domain  and  are  likely  responsible  for  the  increased  Km  for  biotin,  explaining  the  biotin  responsiveness  that  occurs  in  this  disease.  A  mutation  that  results  in  an  enzyme  with  a  normal  Km  but  decreased  Vmax  may  also  respond  to  biotin  supplementation,  and  in  such  cases  it  is  speculated  that  the  enzyme  conformation  is  favorably  affected  by  super-physiologic  biotin  concentration.  A  single  base  deletion/null  mutation  has  always  been  found  in  the  compound  heterozygous  state,  usually  together  with  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
M3  - doi: 10.1036/ommbid.188
Y2  - 2024/10/03
UR  - ommbid.mhmedical.com/content.aspx?aid=1181467801
ER  -