Bernard D. Santarsiero
University of Illinois at Chicago
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Featured researches published by Bernard D. Santarsiero.
Nature Structural & Molecular Biology | 1999
Bostjan Kobe; Ian G. Jennings; Colin M. House; Belinda J. Michell; Kenneth E. Goodwill; Bernard D. Santarsiero; Raymond C. Stevens; Richard G.H. Cotton; Bruce E. Kemp
Phenylalanine hydroxylase converts phenylalanine to tyrosine, a rate-limiting step in phenylalanine catabolism and protein and neurotransmitter biosynthesis. It is tightly regulated by the substrates phenylalanine and tetrahydrobiopterin and by phosphorylation. We present the crystal structures of dephosphorylated and phosphorylated forms of a dimeric enzyme with catalytic and regulatory properties of the wild-type protein. The structures reveal a catalytic domain flexibly linked to a regulatory domain. The latter consists of an N-terminal autoregulatory sequence (containing Ser 16, which is the site of phosphorylation) that extends over the active site pocket, and an α-β sandwich core that is, unexpectedly, structurally related to both pterin dehydratase and the regulatory domains of metabolic enzymes. Phosphorylation has no major structural effects in the absence of phenylalanine, suggesting that phenylalanine and phosphorylation act in concert to activate the enzyme through a combination of intrasteric and possibly allosteric mechanisms.
Tetrahedron | 2002
Bao Ning Su; Rosana Misico; Eun Jung Park; Bernard D. Santarsiero; Andrew D. Mesecar; Harry H. S. Fong; John M. Pezzuto; A. Douglas Kinghorn
Abstract An ethyl acetate-soluble extract of the leaves and stems of Physalis philadelphica has been investigated, leading to the isolation of three new withanolides, philadelphicalactones A ( 1 ) and B ( 2 ), and ixocarpalactone B ( 3 ), four known withanolides, ixocarpalactone A ( 4 ), withaphysacarpin ( 5 ), 18-hydroxywithanolide D ( 6 ), and withanone ( 7 ), one new ceramide, (2S,3S,4R,9E)-1,3,4-trihydroxy-2-[(2′R)-2′-hydroxytetracosanoylamino]-9-octadecene ( 8 ), two known ceramides, (2S,3S,4R)-2-[(2′R)-2′-hydroxytetracosanoylamino]-1,3,4-octadecanetriol ( 9 ), and (2S,3S,4R)-2-tetracosanoylamino-1,3,4-octadecanetriol ( 10 ), as well as the known chlorophyllide a ( 11 ). The structures of the new compounds were elucidated based on spectroscopic and chemical methods. Single-crystal X-ray diffraction analysis was used to confirm the relative stereochemistry of compounds 1 and 4 . The absolute stereochemistry of compounds 1–4 and 8 was established by Mosher ester methodology and chemical transformation. All isolates were evaluated for their potential cancer chemopreventive properties utilizing in vitro assays to determine quinone reductase induction and inhibition of murine epidermal JB6 cell transformation.
Biochemical Journal | 2008
Barbara Calamini; Bernard D. Santarsiero; Jean A. Boutin; Andrew D. Mesecar
Melatonin exerts its biological effects through at least two transmembrane G-protein-coupled receptors, MT1 and MT2, and a lower-affinity cytosolic binding site, designated MT3. MT3 has recently been identified as QR2 (quinone reductase 2) (EC 1.10.99.2) which is of significance since it links the antioxidant effects of melatonin to a mechanism of action. Initially, QR2 was believed to function analogously to QR1 in protecting cells from highly reactive quinones. However, recent studies indicate that QR2 may actually transform certain quinone substrates into more highly reactive compounds capable of causing cellular damage. Therefore it is hypothesized that inhibition of QR2 in certain cases may lead to protection of cells against these highly reactive species. Since melatonin is known to inhibit QR2 activity, but its binding site and mode of inhibition are not known, we determined the mechanism of inhibition of QR2 by melatonin and a series of melatonin and 5-hydroxytryptamine (serotonin) analogues, and we determined the X-ray structures of melatonin and 2-iodomelatonin in complex with QR2 to between 1.5 and 1.8 A (1 A=0.1 nm) resolution. Finally, the thermodynamic binding constants for melatonin and 2-iodomelatonin were determined by ITC (isothermal titration calorimetry). The kinetic results indicate that melatonin is a competitive inhibitor against N-methyldihydronicotinamide (K(i)=7.2 microM) and uncompetitive against menadione (K(i)=92 microM), and the X-ray structures shows that melatonin binds in multiple orientations within the active sites of the QR2 dimer as opposed to an allosteric site. These results provide new insights into the binding mechanisms of melatonin and analogues to QR2.
Phytochemistry | 2010
Shunyan Mo; Aleksej Krunic; Bernard D. Santarsiero; Scott G. Franzblau; Jimmy Orjala
Four hapalindole-related alkaloids, namely fischambiguines A and B, ambiguine P, ambiguine Q nitrile as well as ambiguine G nitrile were identified from the cultured cyanobacterium Fischerella ambigua (UTEX 1903). The structures were determined by spectroscopic analysis including MS, 1D and 2D NMR and X-ray crystallography. The alkaloids possessed fused pentacyclic and hexacyclic carbon skeletons. Fischambiguine B displayed a strong inhibitory activity against Mycobacterium tuberculosis with an MIC value of 2 μM, with no detectable cytotoxicity in a Vero cell line.
Archives of Biochemistry and Biophysics | 2009
Renda Hawwa; John Aikens; Robert J. Turner; Bernard D. Santarsiero; Andrew D. Mesecar
A new enzyme homologous to phosphotriesterase was identified from the bacterium Geobacillus stearothermophilus (GsP). This enzyme belongs to the amidohydrolase family and possesses the ability to hydrolyze both lactone and organophosphate (OP) compounds, making it a phosphotriesterase-like lactonase (PLL). GsP possesses higher OP-degrading activity than recently characterized PLLs, and it is extremely thermostable. GsP is active up to 100 degrees C with an energy of activation of 8.0 kcal/mol towards ethyl paraoxon, and it can withstand an incubation temperature of 60 degrees C for two days. In an attempt to understand the thermostability of PLLs, the X-ray structure of GsP was determined and compared to those of existing PLLs. Based upon a comparative analysis, a new thermal advantage score and plot was developed and reveals that a number of different factors contribute to the thermostability of PLLs.
Tetrahedron Letters | 2002
Sheng Hong Li; Hong-Jie Zhang; Sheng-Xiang Qiu; Xue-Mei Niu; Bernard D. Santarsiero; Andrew D. Mesecar; Harry H. S. Fong; Norman R. Farnsworth; Han-Dong Sun
A novel labdane diterpene alkaloid, vitexlactam A (1) was isolated as a prism from the n-hexane extract of the fruits of Vitex agnus-castus through normal and reverse phase column chromatography. Its structure was elucidated to be 6beta-acetoxy-9alpha-hydroxy-13(14)-labden-16,15-amide, based on chemical and spectral evidences including 1D and 2D NMR spectra. The structure was confirmed by X-ray crystallographic analysis. Compound 1 is the first naturally occurring labdane diterpenoid containing an alpha,beta-unsaturated gamma-lactam moiety
Journal of Molecular Biology | 1994
Catherine A. McPhalen; Anita R. Sielecki; Bernard D. Santarsiero; Michael N. G. James
We present here the X-ray crystal structure of the rat α-parvalbumin from fast twitch muscle. This protein (Mr 11·8kDa) crystallizes in space group P212121 with unit cell dimensions of a=34·3 A, b=55·0 A, c=156·1 A and three molecules in the asymmetric unit. The protein structure was solved by the molecular replacement method and has been refined to a crystallographic R-factor (R=Σ∥Fo|-|Fc∥/Σ|Fo|)) of 0·181 for all reflections with I/σ(I)(l) ≥ 2 (I=intensity) between 8·0 and 2·0 A resolution. The molecules located most easily in the molecular replacement rotation function had lower overall thermal motion parameters and higher numbers of intermolecular crystal packing contacts. The overall fold of the polypeptide chain for the rat α-parvalbumin is similar to other known parvalbumin structures (root-mean-square deviations in α-carbon atom positions range from 0·60 to 0·87 A). There are two Ca2+-binding sites in parvalbumins, and them is some evidence for a third ion-binding site, adjacent to the CD site, in the rat species. The level of structural variability among the best-ordered regions of the three independent rat, α-parvalbumin molecules in the crystallographic asymmetric unit, is two to three times higher than the mean coordinate error (0·10 A), indicating flexibility in the molecule. Sequence differences between α and β-lineage parvalbumins result in repacking of the hydrophobic core and some shifts in the protein backbone. The shifts are localized, however, and entire helices do not shift as rigid units.
Journal of Biological Chemistry | 2010
Shahila Mehboob; Yuanli Song; Marta A. Witek; Fei Long; Bernard D. Santarsiero; Michael E. Johnson; Leslie W.-M. Fung
We have solved the crystal structure of a segment of nonerythroid α-spectrin (αII) consisting of the first 147 residues to a resolution of 2.3 Å. We find that the structure of this segment is generally similar to a corresponding segment from erythroid α-spectrin (αI) but exhibits unique differences with functional significance. Specific features include the following: (i) an irregular and frayed first helix (Helix C′); (ii) a helical conformation in the junction region connecting Helix C′ with the first structural domain (D1); (iii) a long A1B1 loop in D1; and (iv) specific inter-helix hydrogen bonds/salt bridges that stabilize D1. Our findings suggest that the hydrogen bond networks contribute to structural domain stability, and thus rigidity, in αII, and the lack of such hydrogen bond networks in αI leads to flexibility in αI. We have previously shown the junction region connecting Helix C′ to D1 to be unstructured in αI (Park, S., Caffrey, M. S., Johnson, M. E., and Fung, L. W. (2003) J. Biol. Chem. 278, 21837–21844) and now find it to be helical in αII, an important difference for α-spectrin association with β-spectrin in forming tetramers. Homology modeling and molecular dynamics simulation studies of the structure of the tetramerization site, a triple helical bundle of partial domain helices, show that mutations in α-spectrin will affect Helix C′ structural flexibility and/or the junction region conformation and may alter the equilibrium between spectrin dimers and tetramers in cells. Mutations leading to reduced levels of functional tetramers in cells may potentially lead to abnormal neuronal functions.
Phytochemistry | 2003
Bao Ning Su; Young Hwa Kang; Rosa Elena Pinos; Bernard D. Santarsiero; Andrew D. Mesecar; D. Doel Soejarto; Harry H. S. Fong; John M. Pezzuto; A. Douglas Kinghorn
Coussaric acid (1), a triterpenoid based on an ursane skeleton, and an oleanane-type triterpene acid, 3-epi-spathodic acid (2), as well as four known compounds, barbinervic acid, scutellaric acid, stigmasterol and stigmasterol glucoside, have been isolated from an EtOAc-soluble extract of the stems of Coussarea brevicaulis. The structures of compounds 1 and 2 were elucidated on the basis of spectroscopic investigation, and single-crystal X-ray crystallography was used to confirm the structure of 1. The absolute stereochemistry of 1 was established by chemical transformations and by the Mosher ester procedure. The potential of the isolates and chemical transformation products to induce quinone reductase was evaluated in mouse Hepa lclc7 hepatoma cells.
Tetrahedron | 1999
Derrick L. J. Clive; Yunxin Bo; Natesan Selvakumar; Robert McDonald; Bernard D. Santarsiero
Abstract Diels-Alder reaction between ketene acetal 3 and the β-nitroacrylate ester 12 of (−)-8-phenylmenthol gave optically pure ketone 17. This substance was modified in such a way as to remove the chiral auxiliary and afford the epimeric silyl ethers 20M and 20m. Following procedures worked out using racemic materials, both 20M and 20m were converted into optically pure (−)-calicheamicinone (1). This is a crystalline substance, and an X-ray structure determination was carried out.