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@ARTICLE{Bustad:601545,
      author       = {Bustad, Helene J. and Christie, Marthe S. and Laitaoja,
                      Mikko and Aarsand, Aasne K. and Martinez, Aurora and Jänis,
                      Janne and Kallio, Juha P.},
      title        = {{O}ne ring closer to a closure: the crystal structure of
                      the {ES}$_3$ hydroxymethylbilane synthase intermediate},
      journal      = {The FEBS journal},
      volume       = {291},
      number       = {3},
      issn         = {0014-2956},
      address      = {Oxford [u.a.]},
      publisher    = {Wiley-Blackwell},
      reportid     = {PUBDB-2024-00254},
      pages        = {510 - 526},
      year         = {2023},
      note         = {online first},
      abstract     = {Hydroxymethylbilane synthase (HMBS), involved in haem
                      biosynthesis, catalyses the head-to-tail coupling of four
                      porphobilinogens (PBGs) via a dipyrromethane (DPM) cofactor.
                      DPM is composed of two PBGs, and a hexapyrrole is built
                      before the tetrapyrrolic 1-hydroxymethylbilane product is
                      released. During this elongation, stable enzyme (E)
                      intermediates are formed from the holoenzyme, with
                      additional PBG substrates (S): ES, ES$_2$, ES$_3$ and
                      ES$_4$. Native PAGE and mass spectrometry of the acute
                      intermittent porphyria (AIP)-associated HMBS variant
                      p.Arg167Gln demonstrated an increased amount of ES$_3$.
                      Kinetic parameters indicated catalytic dysfunction, however,
                      the product release was not entirely prevented. Isolation
                      and crystal structure analysis of the ES$_3$ intermediate
                      (PDB: 8PND) showed that a pentapyrrole was fully retained
                      within the active site, revealing that polypyrrole
                      elongation proceeds within the active site via a third
                      interaction site, intermediate pyrrole site 3 (IPS3). The
                      AIP-associated HMBS variant p.Arg195Cys, located on the
                      opposite side to p.Arg167Gln in the active site, accumulated
                      the ES$_4$ intermediate in the presence of excess PBG,
                      implying that product hydrolysis was obstructed. Arg167 is
                      thus involved in all elongation steps and is a determinant
                      for the rate of enzyme catalysis, whereas Arg195 is
                      important for releasing the product. Moreover, by
                      substituting residues in the vicinity of IPS3, our results
                      indicate that a fully retained hexapyrrole could be
                      hydrolysed in a novel site in proximity of the IPS3.},
      cin          = {DOOR ; HAS-User},
      ddc          = {610},
      cid          = {I:(DE-H253)HAS-User-20120731},
      pnm          = {6G3 - PETRA III (DESY) (POF4-6G3)},
      pid          = {G:(DE-HGF)POF4-6G3},
      experiment   = {EXP:(DE-H253)P-P11-20150101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37863644},
      UT           = {WOS:001096057200001},
      doi          = {10.1111/febs.16982},
      url          = {https://bib-pubdb1.desy.de/record/601545},
}