PMID- 10590022
OWN - NLM
STAT- MEDLINE
DCOM- 19991227
LR  - 20190915
IS  - 0031-3998 (Print)
IS  - 0031-3998 (Linking)
VI  - 46
IP  - 6
DP  - 1999 Dec
TI  - Relationship between kinetic properties of mutant enzyme and biochemical and
      clinical responsiveness to biotin in holocarboxylase synthetase deficiency.
PG  - 671-6
AB  - Holocarboxylase synthetase (HCS) deficiency is a metabolic disorder that causes a
      biotin-responsive multiple carboxylase deficiency. We analyzed the kinetic
      properties of seven mutant HCS proteins. Two of these enzymes harbored mutations 
      within the putative biotin-binding region of HCS and showed elevated Km values
      for biotin compared with that of the wild-type form (Km mutant; Gly581Ser: 45
      times, delThr610: 3 times). The remaining five mutations (Arg183Pro, Leu216Arg,
      Leu237Pro, Val333Glu, and Val363Asp) were located outside the biotin-binding
      region. The enzymes containing these mutations showed normal or low Km values for
      biotin (non-Km mutant). Symptoms of patients who have the non-Km, mutants, as
      well as those of patients who have the Km, mutants, responded to biotin therapy. 
      This is probably because the Km value for biotin of normal HCS is higher than the
      physiologic concentration of biotin in human cells. The Vmax values of all mutant
      HCS proteins were considerably decreased, but to a variable degree. The
      responsiveness to biotin supplementation of propionyl-CoA carboxylase activity in
      cultured cells bearing the mutations correlated well with the degree of reduction
      in the Vmax of HCS. Patients who have mutant HCS proteins with lower Vmax showed 
      poorer clinical and biochemical responses to biotin therapy. These observations
      suggest that the reduction of Vmax is an essential factor for pathophysiology and
      prognosis of HCS deficiency under treatment with large amounts of biotin. The
      determination of HCS genotype can be valuable for characterizing the clinical
      phenotype in HCS deficient patients.
FAU - Sakamoto, O
AU  - Sakamoto O
AD  - Department of Medical Genetics, Tohoku University School of Medicine, Sendai,
      Japan.
FAU - Suzuki, Y
AU  - Suzuki Y
FAU - Li, X
AU  - Li X
FAU - Aoki, Y
AU  - Aoki Y
FAU - Hiratsuka, M
AU  - Hiratsuka M
FAU - Suormala, T
AU  - Suormala T
FAU - Baumgartner, E R
AU  - Baumgartner ER
FAU - Gibson, K M
AU  - Gibson KM
FAU - Narisawa, K
AU  - Narisawa K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Pediatr Res
JT  - Pediatric research
JID - 0100714
RN  - 6SO6U10H04 (Biotin)
RN  - EC 6.3.- (Carbon-Nitrogen Ligases)
RN  - EC 6.3.4.- (holocarboxylase synthetases)
SB  - IM
MH  - Biotin/*metabolism
MH  - Carbon-Nitrogen Ligases/*deficiency/*genetics
MH  - Child, Preschool
MH  - Female
MH  - Humans
MH  - Infant
MH  - Infant, Newborn
MH  - Kinetics
MH  - Male
MH  - *Mutation
MH  - Substrate Specificity
EDAT- 1999/12/10 00:00
MHDA- 1999/12/10 00:01
CRDT- 1999/12/10 00:00
PHST- 1999/12/10 00:00 [pubmed]
PHST- 1999/12/10 00:01 [medline]
PHST- 1999/12/10 00:00 [entrez]
AID - 10.1203/00006450-199912000-00004 [doi]
PST - ppublish
SO  - Pediatr Res. 1999 Dec;46(6):671-6. doi: 10.1203/00006450-199912000-00004.