RT Book, Section
A1 Hechtman, Peter
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181434814
T1 Prolidase Deficiency
T2 The Online Metabolic and Molecular Bases of Inherited Disease
YR 2019
FD 2019
PB McGraw-Hill Education
PP New York, NY
SN 9780071459969
LK ommbid.mhmedical.com/content.aspx?aid=1181434814
RD 2024/04/18
AB Prolidase  deficiency  (PD)  (MIM  170100)  is  a  rare,  autosomal  recessive,  panethnic  disorder  associated  with  massive  imidodipeptiduria.  Undegraded  dipeptides  are  excreted  in  excess  of  15  mmol/day.  Affected  children  often  present  with  severe  skin  ulcers,  particularly  on  their  hands  and  feet.  Mild  to  severe  mental  retardation  occurs  in  approximately  75  percent  of  cases.  Additionally,  PD  individuals  appear  to  be  highly  susceptible  to  infections,  some  of  which  have  been  fatal.  There  is  considerable  clinical  heterogeneity  and  at  least  five  asymptomatic  PD  individuals  have  been  identified.  Three  of  these  had  severely  affected  sibs  and  two  were  detected  in  newborn  screening  programs.Prolidase  (imidodipeptidase,  peptidase  D;  EC  3.4.13.9)  is  a  ubiquitous  cytosolic  enzyme  that  catalyzes  hydrolysis  of  dipeptides  with  a  C-terminal  proline  or  hydroxyproline.  The  enzyme  is  encoded  by  the  peptidase  D  (PEPD)  gene  located  at  19q12-q13.11.  PEPD  spans  130  kb  and  has  15  exons.  The  2.1  to  2.2  kb  mRNA  is  translated  into  a  493-amino  acid  protein  with  a  predicted  molecular  weight  of  54.3  kDa.  Native  prolidase  is  a  homodimer.  A  second,  less  well-characterized  enzyme  able  to  catalyze  hydrolysis  of  imidodipeptides  is  known  as  prolidase  II.  Its  activity  does  not  appear  to  compensate  for  deficiency  of  prolidase.Prolidase  is  a  metalloenzyme  that  is  activated  by  Mn+2.  The  specificity  and  function  of  prolidase  metal  binding  remains  controversial.  Recent  reports  indicate  that  Mn+2  incubation  affects  the  Vmax  but  not  the  Km  of  prolidase  and  that  Mn+2  also  increases  the  thermostability  of  the  enzyme.  Some  metals,  such  as  Co+2,  Mg+2  and  Fe+2  stimulate  enzyme  activity  to  a  lesser  extent  than  Mn+2;  others,  such  as  Zn+2,  Pb+2,  Hg+2  and  Cd+2,  inhibit  prolidase  activity.A  structural  model  for  prolidase  has  been  proposed  based  on  homology  modeling  with  crystallized  E.  coli  methionine  aminopeptidase.  There  is  a  “pita-bread  fold”  in  which  five  amino  acid  residues  form  two  metal  binding  sites  in  each  subunit.  This  predicted  stoichiometric  ratio  is  supported  by  atomic  absorption  spectroscopy  on  purified,  activated  human  prolidase.  The  catalytic  site  of  prolidase  is  predicted  to  contain  an  arginine  and  an  acidic  amino  acid.Mutation  analysis  in  PD  individuals  has  identified  nine  PEPD  mutations.  Most  are  CpG  mutations  and  only  one,  G448R,  has  been  found  in  multiple,  unrelated  individuals.  Expression  systems  for  testing  the  functional  consequences  of  PEPD  mutations  use  COS  cells  or  NIH3T3  cells.Proline  is  a  nonessential  amino  acid.  Its  biosynthesis  in  human  tissues  occurs  via  the  action  of  Δ-1-pyrroline-5-carboxylic  acid  reductase  upon  glutamic  semialdehyde  (see  Disorders  of  Proline  and  Hydroxyproline  Metabolism).  Both  glutamic  acid  and  arginine  (via  ornithine)  are  precursors.  Studies  in  cultured  fibroblasts  have  shown,  however,  that  these  sources  contribute  to  less  than  10  percent  of  collagen-bound  proline.  This  suggests  a  role  for  prolidase  in  recycling  dipeptide-bound  proline  back  to  the  free  amino  acid  pool  for  utilization  in  protein  biosynthesis.  Prolidase  substrates  can  entirely  satisfy  the  growth  requirements  of  cultured  CHO  cells  auxotrophic  for  proline.The  abundance  of  glycyl-L-proline  (typically  15  to  35  percent  of  excreted  dipeptide)  in  the  urine  of  PD  patients  and  the  presence  of  hydroxyproline-containing  dipeptides  suggests  a  role  for  prolidase  in  collagen  turnover.  The  urine  ofprolidase  deficient  patients  contains  high  concentrations  ...