Scribd Logo
Upload

Welcome to Scribd!

  • 26 views

    MJB Sialic Acid

    Uploaded by

    Saurav Paul
    Sialic acid is a family of acidic sugars that are found widely in animal tissues. The most common form is N-acetylneuraminic acid (Neu5Ac). It was first isolated in 1936 from saliva and brain tissues. Sialic acid plays important biological roles, such as providing most of the negative charge on human red blood cells and serving as a receptor for influenza virus. It is synthesized through an aldol reaction between N-acetylglucosamine and pyruvate. Modern synthesis routes for sialic acid involve retrosynthetic analysis to deconstruct it into readily available starting materials that can recombine to form the target molecule.

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd

    MJB Sialic Acid

    Uploaded by

    Saurav Paul
    26 views25 pages
    Sialic acid is a family of acidic sugars that are found widely in animal tissues. The most common form is N-acetylneuraminic acid (Neu5Ac). It was first isolated in 1936 from saliva and brain tissues. Sialic acid plays important biological roles, such as providing most of the negative charge on human red blood cells and serving as a receptor for influenza virus. It is synthesized through an aldol reaction between N-acetylglucosamine and pyruvate. Modern synthesis routes for sialic acid involve retrosynthetic analysis to deconstruct it into readily available starting materials that can recombine to form the target molecule.

    Copyright

    © © All Rights Reserved

    Available Formats

    PDF, TXT or read online from Scribd

    Did you find this document useful?

    Is this content inappropriate?

    Sialic acid is a family of acidic sugars that are found widely in animal tissues. The most common form is N-acetylneuraminic acid (Neu5Ac). It was first isolated in 1936 from saliva and brain tissues. Sialic acid plays important biological roles, such as providing most of the negative charge on human red blood cells and serving as a receptor for influenza virus. It is synthesized through an aldol reaction between N-acetylglucosamine and pyruvate. Modern synthesis routes for sialic acid involve retrosynthetic analysis to deconstruct it into readily available starting materials that can recombine to form the target molecule.

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    26 views25 pages

    MJB Sialic Acid

    Uploaded by

    Saurav Paul
    Sialic acid is a family of acidic sugars that are found widely in animal tissues. The most common form is N-acetylneuraminic acid (Neu5Ac). It was first isolated in 1936 from saliva and brain tissues. Sialic acid plays important biological roles, such as providing most of the negative charge on human red blood cells and serving as a receptor for influenza virus. It is synthesized through an aldol reaction between N-acetylglucosamine and pyruvate. Modern synthesis routes for sialic acid involve retrosynthetic analysis to deconstruct it into readily available starting materials that can recombine to form the target molecule.

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    of 25

    Sialic Acid

    M Bordoloi

    All are requested to note down in


    their note book
    • Sialic acid is a generic term for a
    family of derivatives of neuraminic
    acid, an acidic sugar with a nine-
    carbon backbone.
    • It is also the name for the most
    common member of this group, i.e. N-
    acetylneuraminic acid (Neu5Ac or
    NANA).
    • Sialic acids are found widely distributed in animal
    tissues and to a lesser extent in other organisms, ranging
    from fungi to yeasts and bacteria, mostly in
    glycoproteins and gangliosides (they occur at the end of
    sugar chains connected to the surfaces of cells and
    soluble proteins)

    • Sialic acid is an important sugar. For instance, it


    accounts for about 95% of the negative charge on the
    surfaces of human erythrocytes. Influenza virus binds to
    the sialic acid of the erythrocytes and other cell
    membranes.
    • It was first isolated by Gunnar Blix from
    salivary mucins in 1936 and then independently
    by Ernst Klenk from brain glycolipids
    (gangliosides) in 1941 (Blix 1936; Klenk 1941).
    • Not knowing they were the same structure, the
    two investigators named the isolated glycan
    independently after saliva (Blix) and neurons
    (Klenk) from which it was isolated
    In the course of the next 25 years, various laboratories
    attempted to determine the structure of the simplest of the
    sialic acids, N-acetylneuraminic acid or NAN [an archaic
    abbreviation for Neu5Ac]. It was so difficult to work with, that
    11 structures were proposed. Finally, the 11th, proposed by
    Gottschalk, was accepted by all workers in the field.

    NAN was a nine carbon sugar acid with a 2-keto, 3-deoxy


    and a 5-acetamido group. In fact, it appeared to be an aldol
    type condensation product of pyruvate and N-
    acetylglucosamine.

    It appeared to be an aldol type condensation product of


    pyruvate and N-acetylglucosamine
    Evidence for Gottschalk formulation for structure of NAN.

    Reaction 1 : Reverse the aldol condensation, and isolated N-acetylglucosamine (N-


    AcGm or GlcNAc) and pyruvate.
    Reaction 2: Kuhn and Brossmer did the same thing with pyridine, nickel and heat
    Reaction 3: Heimer and Meyer treated NAN with an extract from Vibrio cholerae; the
    extract had such a low activity that they incubated it for 2 days and
    obtained only enough to characterize the sugar as GlcNAc (N-AcGm) by
    paper chromatography
    Reaction 4: Aan aldol condensation with GlcNAc and oxaloacetate (pyruvate was not
    sufficiently reactive), and isolated authentic NAN by ion-exchange
    chromatography, albeit in low yield Glycobiology, Volume 27, Issue 6, June 2017, Pages 513–517,
    The sialic acid family includes 43
    derivatives of the nine-carbon sugar
    neuraminic acid, but these acids rarely
    appear free in nature. Normally they can
    be found as components of
    oligosaccharide chains of mucins,
    glycoproteins and glycolipids occupying
    terminal, nonreducing positions of
    complex carbohydrates on both external
    and internal membrane areas where they
    are very exposed and develop important
    functions. The numbering of the sialic
    acid structure begins at the carboxylate
    carbon and continues around the chain.
    The configuration that places the
    carboxylate in the axial position is the
    alpha-anomer.
    The alpha-anomer is the form that is found when sialic acid is bound to glycans. However,
    in solution, it is mainly (over 90%) in the beta-anomeric form. A bacterial enzyme with
    sialic acid mutarotase activity, NanM, that is able to rapidly equilibrate solutions of sialic
    acid to the resting equilibrium position of around 90% beta/10% alpha has been
    discovered
    • Sialic acid-rich glycoproteins (sialoglycoproteins) bind selectin in humans and
    other organisms. Metastatic cancer cells often express a high density of sialic
    acid-rich glycoproteins. This overexpression of sialic acid on surfaces creates a
    negative charge on cell membranes. This creates repulsion between cells (cell
    opposition) and helps these late-stage cancer cells enter the blood stream.
    • Many bacteria also use sialic acid in their biology, although this is usually limited
    to bacteria that live in association with higher animals (deuterostomes). Many of
    these incorporate sialic acid into cell surface features like their lipopolysaccharide
    and capsule, which helps them evade the innate immune response of the host.
    • Sialic acid-rich oligosaccharides on the glycoconjugates (glycolipids,
    glycoproteins, proteoglycans) found on surface membranes help keep water at the
    surface of cells. The sialic acid-rich regions contribute to creating a negative
    charge on the cells' surfaces. Since water is a polar molecule with partial positive
    charges on both hydrogen atoms, it is attracted to cell surfaces and membranes.
    This also contributes to cellular fluid uptake.
    • Sialic acid in the form of polysialic acid is an unusual posttranslational
    modification that occurs on the neural cell adhesion molecules (NCAMs). In the
    synapse, the strong negative charge of the polysialic acid prevents NCAM cross-
    linking of cells.
    Many viruses such as some adenoviruses (Adenoviridae),
    rotaviruses (Reoviridae) and influenza viruses (Orthomyxoviridae)
    can use host-sialylated structures for binding to their target host
    cell. Sialic acids provide a good target for these viruses since they
    are highly conserved and are abundant in large numbers in
    virtually all cells. Unsurprisingly, sialic acids also play an
    important role in several human viral infections. The influenza
    viruses have hemagglutinin activity (HA) glycoproteins on their
    surfaces that bind to sialic acids found on the surface of human
    erythrocytes and on the cell membranes of the upper respiratory
    tract. This is the basis of hemagglutination when viruses are mixed
    with blood cells, and entry of the virus into cells of the upper
    respiratory tract. Widely used anti-influenza drugs (oseltamivir
    and zanamivir) are sialic acid analogs that
    interfere with release of newly generated viruses from infected
    cells by inhibiting the viral enzyme neuraminidase
    2-Keto-3-Deoxy-D-Gycero-D-Galacto-nononic acid
    3-deoxy-D-glycero-D-galacto-2-nonulopyranosonic acid
    Relenza (Zanamivir)
    Tamilflu (Oseltamivir)
    Biosynthesis

    GSH Glutathione
    In bacterial systems, sialic acids are biosynthesized by an
    aldolase enzyme. The enzyme uses a mannose derivative as a
    substrate, inserting three carbons from pyruvate into the
    resulting sialic acid structure. These enzymes can be used for
    chemoenzymatic synthesis of sialic acid derivatives
    Sialic Acid Part II
    M Bordoloi

    All are requested to note down in


    their note book
    Synthesis of Sialic Acid
    • Disconnection: An analytical operation, which breaks
    Retrosynthesis a bond and converts a molecule into a possible starting
    material. The reverse of a chemical reaction. Symbol ⇒
    and a curved line drawn through the bond being broken.
    • FGI: Functional Group Interconversion: The
    operation of writing one functional group for another so that
    disconnection becomes possible. The reverse of a chemical
    reaction. Symbol ⇒ with FGI written over it.
    • Reagent: A compound which reacts to give an
    intermediate in the planned synthesis or to give the target
    molecule itself. The synthetic equivalent of a synthon.
    • Synthetic equivalent: A reagent carrying out the
    function of a synthon which cannot itself be used, often
    because it is too unstable.
    •Synthon: A generalized fragment, usually an ion,
    produced by a disconnection. (some people also use
    synthon for a synthetic equivalent).
    •Target Molecule: The molecule whose synthesis is
    being planned.
    Synthesis of Sialic Acid
    Retrosynthesis
    Retrosynthesis is the process of
    “deconstructing” a target molecule into readily
    available starting materials by means of :
    -imaginary breaking of bonds (disconnections) and
    - by the conversion of one functional group into
    another (functional group interconversions).
    Synthesis of Sialic Acid
    Retrosynthesis
    Retrosynthesis ?
    Synthesis of Sialic Acid
    Retrosynthesis
    Petasis coupling
    (E)-N-(2-ethoxy-2-
    oxoethylidene)methanamine
    oxide

    L-Neu5Ac
    Overall yield 60%
    Sulfamate ester 1 was prepared from tri-
    O-acetyl glucal and treated with PhIO,
    MgO, and rhodium(II) trifluoroacetamide
    ([Rh2(tfacam)4]; 5 mol%) in CH2Cl2 at
    room temperature, under N2.
    This reaction generated a nitrene in situ,
    which added intramolecularly to the C=C
    bond of the glycal. Trapping the resulting
    transient aziridine 2 with an appropriate
    carbon nucleophile was critical. Barbier
    allylation or propargylation has emerged
    as a powerful method for forming CC
    bonds
    D- Neu5Ac,
    Overall yield 60%

    You might also like