TY  - CHAP
M1  - Book, Section
TI  - Vitamin B6 Metabolism and Inborn Errors
A1  - Mills, Philippa B.
A1  - Footitt, Emma J.
A1  - Clayton, Peter T.
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
PY  - 2019
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - Pyridoxal  5′-phosphate  (PLP),  the  active  form  of  vitamin  B6,  is  the  cofactor  for  over  140  enzyme  catalysed  reactions.  For  most  of  these  reactions,  an  amino  acid  is  the  substrate  or  one  of  the  substrates.  Thus  PLP-catalysed  reactions  play  a  central  role  in  amino  acid  metabolism,  including  the  synthesis  and/or  catabolism  of  neurotransmitter  amino  acids  and  amines  in  the  brain.  Reduced  levels  of  PLP  in  the  brain  can  cause  epilepsy,  probably  as  a  consequence  of  the  neurotransmitter  abnormalities.Vitamin  B6  can  be  present  in  the  diet  as  pyridoxal,  pyridoxamine  and  pyridoxine,  their  5′-phosphate  derivatives  and,  in  the  case  of  pyridoxine,  as  a  5′-glucoside.  The  phosphate  and  glucoside  derivatives  are  cleaved  by  intestinal  hydrolases  prior  to  absorption  of  B6  as  pyridoxal,  pyridoxamine  and  pyridoxine.Conversion  of  pyridoxal,  pyridoxamine  and  pyridoxine  to  their  5′-phosphate  derivatives  in  the  liver  requires  pyridoxal  kinase.  Pyridoxamine  5′-phosphate  and  pyridoxine  5′-phosphate  are  then  converted  to  pyridoxal  5′-phosphate  by  pyridox(am)ine  phosphate  oxidase  (PNPO).Pyridoxal  5′-phosphate  generated  in  the  liver  is  the  principal  circulating  form  of  vitamin  B6;  in  plasma  much  of  the  vitamer  is  bound  to  albumin.  Prior  to  entry  into  organs  such  as  the  brain,  pyridoxal  5′-phosphate  is  cleaved  by  the  ectoenzyme,  tissue  non-specific  alkaline  phosphatase.  Once  in  the  brain  pyridoxal  is  rephosphorylated  by  pyridoxal  kinase.Catabolism  of  pyridoxal  5′phosphate  involves  the  action  of  a  phosphatase  producing  pyridoxal  and  then  an  aldehyde  oxidase  or  aldehyde  dehydrogenase  producing  4-pyridoxic  acid  which  is  excreted  in  the  urine.  A  number  of  phosphatases  are  active  on  PLP.  These  include  pyridoxal  phosphatase,  the  alkaline  phosphatases,  acid  phosphatases  and  the  PHOSPHO2  gene  product.  The  relative  importance  of  these  different  phosphatases  in  PLP  homeostasis  in  different  tissues  is  not  known.The  concentrations  of  pyridoxal  5′-phosphate  and  pyridoxal  in  tissues  and  body  fluids  are  regulated  by  the  activity  of  the  phosphatases  and  kinases.  Some  additional  regulation  may  occur  through  PNPO  which  regenerates  pyridoxal  phosphate  from  pyridoxamine  phosphate.  Whole  body  B6  homeostasis  involves  activation  of  the  catabolic  pathway;  when  ingestion  of  B6  is  in  excess  of  needs,  the  excess  B6  is  excreted  as  4′-pyridoxic  acid.Reduced  expression  of  tissue  non-specific  alkaline  phosphatase  (hypophosphatasia)  leads  to  high  levels  of  PLP  in  plasma  but  to  low  levels  in  the  brain  and  hence  to  B6-responsive  epilepsy.  This  highlights  the  importance  of  (TNSALP)  in  mediating  transport  of  PLP  from  blood  to  the  cells  of  the  brain.The  concentration  of  pyridoxal  5′-phosphate  in  the  liver  shows  a  marked  circadian  fluctuation;  a  lesser  degree  of  circadian  variation  occurs  in  the  brain.  In  the  daily  cycle,  increased  levels  of  PLP  are  achieved  by  activation  of  pyridoxal  kinase  by  three  PAR  bZip  transcription  factors,  DBP  (albumin  D-site-binding  protein),  HLF  (hepatic  leukaemia  factor)  and  TEF  (thyrotroph  embryonic  factor).  Knockout  of  these  three  transcription  factors  in  the  mouse  leads  to  seizures  with  a  low  concentration  of  PLP  in  the  brain.PNPO  deficiency  in  man  causes  a  severe,  potentially  fatal,  seizure  disorder  that  is  resistant  to  treatment  with  anticonvulsant  drugs  and  pyridoxine  but  responds  dramatically  to  treatment  with  pyridoxal  5′-phosphate.  It  is  caused  by  recessive  mutations  in  the  PNPO  gene  on  chromosome  17q21.32.Many  of  the  first  described  cases  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/25
UR  - ommbid.mhmedical.com/content.aspx?aid=1181468004
ER  -