PMID- 38542347
OWN - NLM
STAT- MEDLINE
DCOM- 20240329
LR  - 20240330
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 25
IP  - 6
DP  - 2024 Mar 16
TI  - Molecular Modeling of the Multiple-Substrate Activity of the Human Recombinant 
      Intra-Melanosomal Domain of Tyrosinase and Its OCA1B-Related Mutant Variant 
      P406L.
LID - 10.3390/ijms25063373 [doi]
LID - 3373
AB  - Tyrosinase serves as the key enzyme in melanin biosynthesis, catalyzing the 
      initial steps of the pathway, the hydroxylation of the amino acid L-tyrosine into 
      L-3,4-dihydroxyphenylalanine (L-DOPA), followed by the subsequent oxidation of 
      L-DOPA into dopaquinone (DQ), and it facilitates the conversion of 
      5,6-dihydroxyindole-2-carboxylic acid (DHICA) into 5,6-indolequinone-2-carboxylic 
      acid (IQCA) and 5,6-dihydroxy indole (DHI) into indolequinone (IQ). Despite its 
      versatile substrate capabilities, the precise mechanism underlying tyrosinase's 
      multi-substrate activity remains unclear. Previously, we expressed, purified, and 
      characterized the recombinant intra-melanosomal domain of human tyrosinase 
      (rTyr). Here, we demonstrate that rTyr mimics native human tyrosinase's catalytic 
      activities in vitro and in silico. Molecular docking and molecular dynamics (MD) 
      simulations, based on rTyr's homology model, reveal variable durability and 
      binding preferences among tyrosinase substrates and products. Analysis of root 
      mean square deviation (RMSD) highlights the significance of conserved residues 
      (E203, K334, F347, and V377), which exhibit flexibility during the ligands' 
      binding. Additionally, in silico analysis demonstrated that the OCA1B-related 
      P406L mutation in tyrosinase substantially influences substrate binding, as 
      evidenced by the decreased number of stable ligand conformations. This 
      correlation underscores the mutation's impact on substrate docking, which aligns 
      with the observed reduction in rTyr activity. Our study highlights how rTyr 
      dynamically adjusts its structure to accommodate diverse substrates and suggests 
      a way to modulate rTyr ligand plasticity.
FAU - Dolinska, Monika B
AU  - Dolinska MB
AUID- ORCID: 0000-0002-2427-1118
AD  - National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
FAU - Sergeev, Yuri V
AU  - Sergeev YV
AUID- ORCID: 0000-0002-7204-6572
AD  - National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
LA  - eng
GR  - ZIA EY000476-10/EY/NEI NIH HHS/United States
PT  - Journal Article
DEP - 20240316
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - EC 1.14.18.1 (Monophenol Monooxygenase)
RN  - 0 (Melanins)
RN  - 46627O600J (Levodopa)
RN  - 0 (Ligands)
RN  - 0 (Indolequinones)
SB  - IM
MH  - Humans
MH  - *Monophenol Monooxygenase/metabolism
MH  - Melanins/metabolism
MH  - Levodopa
MH  - Molecular Docking Simulation
MH  - Ligands
MH  - *Indolequinones
PMC - PMC10969854
OTO - NOTNLM
OT  - OCA1B albinism
OT  - melanin pathway
OT  - molecular docking
OT  - molecular dynamic simulation
OT  - mutations
OT  - tyrosinase
COIS- The authors declare no conflicts of interest. The funders had no role in the 
      design of the study; in the collection, analyses, or interpretation of the data; 
      in the writing of the manuscript; or in the decision to publish the results.
EDAT- 2024/03/28 06:44
MHDA- 2024/03/29 06:45
PMCR- 2024/03/16
CRDT- 2024/03/28 01:18
PHST- 2024/01/04 00:00 [received]
PHST- 2024/02/27 00:00 [revised]
PHST- 2024/03/12 00:00 [accepted]
PHST- 2024/03/29 06:45 [medline]
PHST- 2024/03/28 06:44 [pubmed]
PHST- 2024/03/28 01:18 [entrez]
PHST- 2024/03/16 00:00 [pmc-release]
AID - ijms25063373 [pii]
AID - ijms-25-03373 [pii]
AID - 10.3390/ijms25063373 [doi]
PST - epublish
SO  - Int J Mol Sci. 2024 Mar 16;25(6):3373. doi: 10.3390/ijms25063373.