TY  - CHAP
M1  - Book, Section
TI  - Disorders of Proline and Hydroxyproline Metabolism
A1  - Phang, James M.
A1  - Hu, Chien-an A.
A1  - Valle, David
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
Y1  - 2019
N1  - 10.1036/ommbid.391
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - Δ-Pyrroline-5-carboxylate  (P5C)  is  both  the  immediate  precursor  and  the  degradation  product  of  proline  and  is  found  not  only  intracellularly  but  also  circulating  in  plasma.  P5C  reductase  (EC  1.5.1.2)  catalyzes  the  conversion  of  P5C  to  proline  as  the  committed  step  in  biosynthesis.  Proline  oxidase  (no  EC  number  assigned)  catalyzes  the  degradation  of  proline  to  P5C.  Other  sources  of  P5C  are  ornithine  and  glutamate  in  reactions  catalyzed  by  ornithine-δ-aminotransferase  (OAT)  (EC  2.6.1.13)  and  P5C  synthase  (no  EC  number  assigned),  respectively.  The  P5C  “outflow”  is  primarily  to  glutamate  in  a  reaction  catalyzed  by  P5C  dehydrogenase  (EC  1.5.1.12).  The  interconversions  of  P5C  and  proline  constitute  a  cycle  for  transferring  reducing-oxidizing  potential  between  cellular  organelles  and  between  tissues.Two  inherited  disorders  in  the  degradative  limb  of  the  proline  metabolic  system  result  in  hyperprolinemia.  Type  I  hyperprolinemia  (HPI)  (MIM  239500)  is  caused  by  deficiency  of  proline  oxidase,  and  type  II  hyperprolinemia  (HPII)  (MIM  239510)  is  due  to  a  deficiency  of  P5C  dehydrogenase;  both  are  apparently  inherited  as  autosomal  recessive  traits.  Proline  levels  are  elevated  three-  to  fivefold  in  the  former  condition  and  ten-  to  fifteenfold  in  the  latter.  The  distinguishing  biochemical  characteristics  in  HPII  are  high  plasma  P5C  levels  and  urinary  excretion  of  P5C.Although  the  metabolic  derangements  in  the  hyperprolinemias  are  consistent  with  normal  adult  life,  there  appears  to  be  a  causal  relationship  between  HPII  and  neurologic  manifestations  in  childhood.  Attempts  at  therapy  by  nutritional  manipulation  have  been  ineffective  because  the  interconversions  of  the  precursors  makes  it  impossible  to  lower  P5C  or  proline  to  any  significant  degree.A  newly  recognized  disorder  apparently  related  to  the  synthetic  limb  of  this  metabolic  system  has  been  described  in  two  sibs  with  mental  retardation,  cataracts,  joint  hyperlaxity,  and  skin  hyperelasticity.  The  biochemical  phenotype,  which  includes  hypoprolinemia,  hypocitrullinemia,  hypoornithinemia,  and  hyperammonemia,  is  consistent  with  a  deficiency  of  P5C  synthase.  No  direct  measurements  of  P5C  synthase  activity  in  tissues  from  these  patients  have  been  described.4-Hydroxy-L-proline  is  not  synthesized  as  the  free  imino  acid.  Rather,  it  is  produced  by  hydroxylation  of  the  third-position  proline  in  the  prevalent  Gly-Pro-Pro  tripeptide  of  the  procollagen  polypeptide  chain.  Free  hydroxyproline  is  derived  from  endogenous  collagen  turnover  and  from  breakdown  of  dietary  collagen.  The  hydroxyproline  degradation  pathway  resembles  that  of  proline.  Δ1-Pyrroline-3-hydroxy-5-carboxylate,  the  oxidation  product  of  hydroxyproline,  is  dehydrogenated  to  4-erythro-hydroxy-L-glutamate.  Transamination  with  oxaloacetate  results  in  4-hydroxy-2-ketoglutarate,  which  is  then  cleaved  to  glyoxalate  and  pyruvate  in  an  aldolase  reaction.  The  enzymes  catalyzing  these  reactions  are  distinct  from  those  for  the  degradation  of  proline,  with  one  exception:  dehydrogenation  of  P5C  and  hydroxy-P5C  is  catalyzed  by  the  same  enzyme,  P5C  dehydrogenase.Hyperhydroxyprolinemia  (MIM  237000)  is  an  autosomal  recessive  trait  resulting  from  a  deficiency  of  hydroxyproline  oxidase  (no  EC  number  assigned).  This  biochemical  disturbance  apparently  has  no  clinical  consequence.  The  metabolism  of  proline  and  collagen  are  normal.  
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
M3  - doi: 10.1036/ommbid.391
Y2  - 2024/04/18
UR  - ommbid.mhmedical.com/content.aspx?aid=1181434663
ER  -