Yoshitaka Ichikawa
Johns Hopkins University School of Medicine
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Featured researches published by Yoshitaka Ichikawa.
Analytical Biochemistry | 1992
Yoshitaka Ichikawa; Gary C. Look; Chi-Huey Wong
Cell-surface carbohydrates and their conjugates are involved in many types of molecular recognition. This review describes recent developments in enzyme-catalyzed oligosaccharide synthesis, with particular focus on glycosyltransferase and glycosidase reactions. With the increasing availability of glycosyltransferases via recombinant DNA technology, glycosyltransferase-catalyzed glycosylation with in situ regeneration of sugar nucleotides appears to be the most effective method for large-scale stereocontrolled oligosaccharide synthesis.
The EMBO Journal | 2000
Thomas Hollis; Yoshitaka Ichikawa; Tom Ellenberger
The Escherichia coli AlkA protein is a base excision repair glycosylase that removes a variety of alkylated bases from DNA. The 2.5 Å crystal structure of AlkA complexed to DNA shows a large distortion in the bound DNA. The enzyme flips a 1‐azaribose abasic nucleotide out of DNA and induces a 66° bend in the DNA with a marked widening of the minor groove. The position of the 1‐azaribose in the enzyme active site suggests an SN1‐type mechanism for the glycosylase reaction, in which the essential catalytic Asp238 provides direct assistance for base removal. Catalytic selectivity might result from the enhanced stacking of positively charged, alkylated bases against the aromatic side chain of Trp272 in conjunction with the relative ease of cleaving the weakened glycosylic bond of these modified nucleotides. The structure of the AlkA–DNA complex offers the first glimpse of a helix–hairpin–helix (HhH) glycosylase complexed to DNA. Modeling studies suggest that other HhH glycosylases can bind to DNA in a similar manner.
FEBS Journal | 2006
Hui-Hwa Chang; Naoki Asano; Satoshi Ishii; Yoshitaka Ichikawa; Jian-Qiang Fan
Gaucher disease is an autosomal recessive lysosomal storage disorder caused by the deficient activity of glucocerebrosidase. Accumulation of glucosylceramide, primarily in the lysosomes of cells of the reticuloendothelial system, leads to hepatosplenomegaly, anemia and skeletal lesions in type I disease, and neurologic manifestations in types II and III disease. We report herein the identification of hydrophilic active‐site‐specific chaperones that are capable of increasing glucocerebrosidase activity in the cultured fibroblasts of Gaucher patients. Screening of a variety of natural and synthetic alkaloid compounds showed isofagomine, N‐dodecyl deoxynojirimycin, calystegines A3, B1, B2 and C1, and 1,5‐dideoxy‐1,5‐iminoxylitol to be potent inhibitors of glucocerebrosidase. Among them, isofagomine was the most potent inhibitor of glucocerebrosidase in vitro, and the most effective active‐site‐specific chaperone capable of increasing residual glucocerebrosidase activity in fibroblasts established from Gaucher patients with the most prevalent Gaucher disease‐causing mutation (N370S). Intracellular enzyme activity increased approximately two‐fold after cells had been incubated with isofagomine, and the increase in glucocerebrosidase activity was both dose‐dependent and time‐dependent. Western blotting demonstrated that there was a substantial increase in glucocerebrosidase protein in cells after isofagomine treatment. Immunocytochemistry revealed an improvement in the glucocerebrosidase trafficking pattern, which overlaps that of lysosome‐associated membrane protein 2 in Gaucher fibroblasts cultivated with isofagomine, suggesting that the transport of mutant glucocerebrosidase is at least partially improved in the presence of isofagomine. The hydrophilic active‐site‐specific chaperones are less toxic to cultured cells. These results indicate that these hydrophilic small molecules are suitable candidates for further drug development for the treatment of Gaucher disease.
Nature Chemical Biology | 2012
Mary Katherine Tarrant; Hee Sool Rho; Zhi Xie; Yu Lin Jiang; Christopher Gross; Jeffrey C. Culhane; Gai Yan; Jiang Qian; Yoshitaka Ichikawa; Tatsuji Matsuoka; Natasha E. Zachara; Felicia A. Etzkorn; Gerald W. Hart; Jun Seop Jeong; Seth Blackshaw; Heng Zhu; Philip A. Cole
Protein Ser/Thr kinase CK2 (casein kinase II) is involved in a myriad of cellular processes including cell growth and proliferation by phosphorylating hundreds of substrates, yet the regulation process of CK2 function is poorly understood. Here we report that the CK2 catalytic subunit CK2α is modified by O-GlcNAc on Ser347, proximal to a cyclin-dependent kinase phosphorylation site (Thr344) on the same protein. We use protein semisynthesis to show that Thr344 phosphorylation increases CK2α cellular stability via Pin1 interaction whereas Ser347 glycosylation appears to be antagonistic to Thr344 phosphorylation and permissive to proteasomal degradation. By performing kinase assays with the site-specifically modified phospho- and glyco-modified CK2α in combination with CK2β and Pin1 binding partners on human protein microarrays, we show that CK2 kinase substrate selectivity is modulated by these specific posttranslational modifications. This study suggests how a promiscuous protein kinase can be regulated at multiple levels to achieve particular biological outputs.
Archives of Biochemistry and Biophysics | 1992
Reiko T. Lee; Yoshitaka Ichikawa; Toshisuke Kawasaki; Kurt Drickamer; Yuan C. Lee
The serum-type mannose-binding protein (MBP) is a defense molecule that has carbohydrate-dependent bactericidal effects. It shares with mammalian and chicken hepatic lectins similarity in the primary structure of the carbohydrate-recognition domain, as well as the ligand-binding mode: a high affinity (KD approximately nM) is generated by clustering of approximately 30 terminal target sugar residues on a macromolecule, such as bovine serum albumin, although the individual monosaccharides have low affinity (KD 0.1-1 mM). On the other hand, MBP does not manifest any significant affinity enhancement toward small, di- and trivalent ligands, in contrast to the hepatic lectins whose affinity toward divalent ligands of comparable structures increased from 100- to 1000-fold. Such differences may be explained on the basis of different subunit organization between the hepatic lectins and MBP.
Methods in Enzymology | 1994
Yoshitaka Ichikawa; Ruo Wang; Chi-Huey Wong
Publisher Summary Glycosyltransferase-mediated oligosaccharide synthesis is of current interest in synthetic carbohydrate chemistry. Although the enzymatic method is regio- and stereoselective and does not require multiple protection and deprotection steps, it is still hampered by the unavailability of transferases, the problem of product inhibition in stoichiometric reactions, and the tedious preparation of the donor substrate sugar nucleotides when large-scale processes are needed. Although many glycosyltransferases are involved in the biosynthesis of oligosaccharides, these enzymes utilize only eight sugar nucleotides as donor substrates in mammalian systems. Development of regeneration systems for each of these sugar nucleotides would therefore make possible the practical synthesis of most complex oligosaccharides, provided that glycosyltransferases are available.
Tetrahedron Letters | 1995
Yoshitaka Ichikawa; Yasuhiro Igarashi
A new galactose-type iminosugar in which a nitrogen atom is in the anomeric position was synthesized and was found to be an extremely potent inhibitor for β-galactosidase with Ki = 4 nM.
Tetrahedron Letters | 1993
Guido F. Herrmann; Yoshitaka Ichikawa; Christian Wandrey; Federico C. A. Gaeta; James C. Paulson; Chi-Huey Wong
An irreversible one-pot enzymatic synthesis of sialyl oligosaccharides has been achieved with a β-galactosidase-catalyzed galactosylation of an acceptor followed by a sialyltransferase-catalyzed sialylation with regeneration in situ of CMP-sialic acid.
Tetrahedron Letters | 1996
Yoshitomo Suhara; James E.K. Hildreth; Yoshitaka Ichikawa
Abstract Readily access to a new class of carbohydrate mimetics has been demonstrated from a d -glucosamine derivative by the synthesis of a tetrameric carbopeptoid in which the glycosidic bonds are replaced with amido linkages.
Bioorganic & Medicinal Chemistry | 1999
Shuichi Takayama; Sang J. Chung; Yasuhiro Igarashi; Yoshitaka Ichikawa; Armin Sepp; Robert I. Lechler; Jiangyue Wu; Takashi Hayashi; Gary Siuzdak; Chi-Huey Wong
A combined rational and library approach was used to identify bisphosphonates (IC50 = 20 microM) and galactose type 1-N-iminosugar (IC50=45 microM) as novel motifs for selective inhibition of beta-1,4-galactosyltransferase (beta-1,4-GalT) and alpha-1,3-galactosyltransferase (alpha-1,3-GalT), respectively. Our results demonstrate that, though these two galactosyltransferases both utilize the same donor sugar-nucleotide (UDP-Gal), the difference in their mechanisms can be utilized to design donor sugar or nucleotide analogues with inhibitory activities selective for only one of the galactosyltransferases. Investigation of beta-1,4-GalT inhibition using UDP-2-deoxy-2-fluorogalactose (UDP-2-F-Gal), UDP, and bisphosphonates, also led to the observation of metal dependent inhibition of beta-1,4-GalT. These observations and the novel inhibitor motifs identified in this study pave the way for the design and identification of even more potent and selective galactosyltransferase inhibitors.