| 1. |
- Collins, Ruairi, et al.
(författare)
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Biochemical discrimination between selenium and sulfur 1 : a single residue provides selenium specificity to human selenocysteine lyase
- 2012
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Ingår i: PLoS One. - Stockholm : Karolinska Institutet, Dept of Medical Biochemistry and Biophysics. - 1932-6203.
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Tidskriftsartikel (refereegranskat)abstract
- Selenium and sulfur are two closely related basic elements utilized in nature for a vast array of biochemical reactions. While toxic at higher concentrations, selenium is an essential trace element incorporated into selenoproteins as selenocysteine (Sec), the selenium analogue of cysteine (Cys). Sec lyases (SCLs) and Cys desulfurases (CDs) catalyze the removal of selenium or sulfur from Sec or Cys and generally act on both substrates. In contrast, human SCL (hSCL) is specific for Sec although the only difference between Sec and Cys is the identity of a single atom. The chemical basis of this selenium-over-sulfur discrimination is not understood. Here we describe the X-ray crystal structure of hSCL and identify Asp146 as the key residue that provides the Sec specificity. A D146K variant resulted in loss of Sec specificity and appearance of CD activity. A dynamic active site segment also provides the structural prerequisites for direct product delivery of selenide produced by Sec cleavage, thus avoiding release of reactive selenide species into the cell. We thus here define a molecular determinant for enzymatic specificity discrimination between a single selenium versus sulfur atom, elements with very similar chemical properties. Our findings thus provide molecular insights into a key level of control in human selenium and selenoprotein turnover and metabolism.
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| 2. |
- Corden, V.A., et al.
(författare)
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Spectroscopic and structural investigations reveal the signaling mechanism of a luminescent molybdate sensor
- 2011
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Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 50:3, s. 1105-1115
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Tidskriftsartikel (refereegranskat)abstract
- A heteroditopic ligand H 2-L consisting of a dihydroxybenzene (catechol)-unit linked via an amide bond to a pyridyl-unit and its methyl-protected precursor Me 2-L were synthesized, characterized, and their photophysical properties investigated. The three accessible protonation states of the ligand, H 2-L+, H 2-L, and H-L-, showed distinct 1 H NMR, absorption and emission spectroscopic characteristics that allow pH-sensing. The spectroscopic signatures obtained act as a guide to understand the signaling mechanism of the luminescent pH and molybdate sensor [Re-(bpy)(CO) 3(H 2-L)]+. It was found that upon deprotonation of the 2-hydroxy group of H 2-L, a ligand-based absorption band emerges that overlaps with the Re(dπ)-bpy metal-to-ligand charge transfer (MLCT) band of the sensor, reducing the quantum yield for emission on excitation in the 370 nm region. In addition, deprotonation of the catechol-unit leads to quenching of the emission from the Re(dn)→ bpy 3MLCT state, consistent with photoinduced electron transfer from the electron-rich, deprotonated catecholate to the Re-based luminophore. Finally, reaction of 2 equiv of [Re(bpy)(CO) 3(H 2-L)]+ with molybdate was shown to give the zwitterionic Mo(VI) complex [MoO 2{Re(CO) 3-(bpy)(L)} 2], as confirmed by electrospray ionization (ESI) mass spectrometry and X-ray crystallography. The crystal structure determination revealed that two fully deprotonated sensor molecules are bound via their oxygen-donors to a cis-dioxo-MoO 2 center.
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| 3. |
- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 4. |
- Heilbronner, Goetz, et al.
(författare)
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Seeded strain-like transmission of beta-amyloid morphotypes in APP transgenic mice
- 2013
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Ingår i: EMBO Reports. - : NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND. - 1469-221X .- 1469-3178. ; 14:11, s. 1017-1022
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Tidskriftsartikel (refereegranskat)abstract
- The polymorphic beta-amyloid lesions present in individuals with Alzheimers disease are collectively known as cerebral beta-amyloidosis. Amyloid precursor protein (APP) transgenic mouse models similarly develop beta-amyloid depositions that differ in morphology, binding of amyloid conformation-sensitive dyes, and A beta 40/A beta 42 peptide ratio. To determine the nature of such beta-amyloid morphotypes, beta-amyloid-containing brain extracts from either aged APP23 brains or aged APPPS1 brains were intracerebrally injected into the hippocampus of young APP23 or APPPS1 transgenic mice. APPPS1 brain extract injected into young APP23 mice induced beta-amyloid deposition with the morphological, conformational, and A beta 40/A beta 42 ratio characteristics of beta-amyloid deposits in aged APPPS1 mice, whereas APP23 brain extract injected into young APP23 mice induced b-amyloid deposits with the characteristics of beta-amyloid deposits in aged APP23 mice. Injecting the two extracts into the APPPS1 host revealed a similar difference between the induced beta-amyloid deposits, although less prominent, and the induced deposits were similar to the beta-amyloid deposits found in aged APPPS1 hosts. These results indicate that the molecular composition and conformation of aggregated A beta in APP transgenic mice can be maintained by seeded conversion.
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