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    Lecture 02 - Natural Products & Biosynthesis, Web

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    Rajesh Kumar
    The document discusses natural products and secondary metabolism. It covers four main topics: (1) toxins from plants like deadly nightshade and mandrake traditionally used for medicine or poison, (2) medicinal plants like willow and cinchona that were the basis for modern drugs like aspirin and quinine, (3) stimulant plants like coca, caffeine, and tobacco, and (4) hallucinogenic plants like opium poppy and mushrooms that contain morphine, LSD, and psilocybin. It also describes the key biochemical pathways like shikimate and terpenes that produce these medically important secondary metabolites.

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    Download as PPT, PDF, TXT or read online from Scribd

    Lecture 02 - Natural Products & Biosynthesis, Web

    Uploaded by

    Rajesh Kumar
    184 views32 pages
    The document discusses natural products and secondary metabolism. It covers four main topics: (1) toxins from plants like deadly nightshade and mandrake traditionally used for medicine or poison, (2) medicinal plants like willow and cinchona that were the basis for modern drugs like aspirin and quinine, (3) stimulant plants like coca, caffeine, and tobacco, and (4) hallucinogenic plants like opium poppy and mushrooms that contain morphine, LSD, and psilocybin. It also describes the key biochemical pathways like shikimate and terpenes that produce these medically important secondary metabolites.

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    The document discusses natural products and secondary metabolism. It covers four main topics: (1) toxins from plants like deadly nightshade and mandrake traditionally used for medicine or poison, (2) medicinal plants like willow and cinchona that were the basis for modern drugs like aspirin and quinine, (3) stimulant plants like coca, caffeine, and tobacco, and (4) hallucinogenic plants like opium poppy and mushrooms that contain morphine, LSD, and psilocybin. It also describes the key biochemical pathways like shikimate and terpenes that produce these medically important secondary metabolites.

    Copyright:

    Attribution Non-Commercial (BY-NC)
    Download as PPT, PDF, TXT or read online from Scribd
    Download as ppt, pdf, or txt
    184 views32 pages

    Lecture 02 - Natural Products & Biosynthesis, Web

    Uploaded by

    Rajesh Kumar
    The document discusses natural products and secondary metabolism. It covers four main topics: (1) toxins from plants like deadly nightshade and mandrake traditionally used for medicine or poison, (2) medicinal plants like willow and cinchona that were the basis for modern drugs like aspirin and quinine, (3) stimulant plants like coca, caffeine, and tobacco, and (4) hallucinogenic plants like opium poppy and mushrooms that contain morphine, LSD, and psilocybin. It also describes the key biochemical pathways like shikimate and terpenes that produce these medically important secondary metabolites.

    Copyright:

    Attribution Non-Commercial (BY-NC)
    Download as PPT, PDF, TXT or read online from Scribd
    Download as ppt, pdf, or txt
    of 32

    Bratton, Heather Bui, Steven

    Bautista, Candie Chen, John

    Chem 444
    Chan, Hiu Fai Doan, Chad Ho, Joyce Karimbabai Massihi, Anna Krasner, Danielle Loi, William Chida, Odette Cueva, Carla Golanbar, Gelareh

    Biol 444

    Kashiwabara, Claudine Kopilec, Jaimisyn Lau, Jensen

    Malette, Jacqueline
    Nguyen, Trang Robles, Marisa Tallorin, Lorillee Truong, Daniel C Udeh, Francis Villalvazo, Adrianne Yeh, Enrenn

    Le, Giang-Tuong
    Lee, Margaret Mata, Francisca Nguyen, Thuy Nhi Phillips, Irving Romero, Marcelo Wang, Tony Wittig, Michelle

    Primary (1) Metabolism


    - Construct common biological macromolecules from simple building blocks found within every cell - Typically a process of polymerization, stringing monomers together into a macromolecule that performs a cellular function sugars amino acids fats polysaccharides proteins phospholipid bilayers

    - Block production: cell dies (primary metabolites are essential)

    Secondary (2) Metabolism


    - Synthesize compounds that are unique to a particular species or genus (unlike common proteins, lipids, etc.) - Molecules may have extremely complex structures - These molecules typically have no effect on the producing organism, but are often highly biologically active against other organisms (competitors, pathogens, predators) - Often present at extraordinary concentrations, >10% of the dry weight of the organism inference is, they must do something

    Natural Products: Folk to Modern Medicines


    - Humans have long used chemicals in plant and animal extracts for many purposes: medicines, poisons, recreational stimulants - Since the 1800s, chemists have characterized and synthesized such natural products, uncovering the basis for folk remedies

    - Identifying the mechanism of action of natural products was the genesis of modern drug discovery - The active ingredients in many ancient curatives are still used medicinally today

    Natural Products 1: Toxins

    Rotenone

    - Natural fish + insect poison


    Curare (Tubocurarine chloride) - Derived from 2 South American plant genera

    - Used as arrow-tip poison by native peoples - Blocks transmission of acetylcholine signal to muscles, causing instant paralysis - 1st drug used as muscle relaxant in surgery

    Natural Products 1: Toxins


    Hyoscine (= scopolamine)

    - Derived from plants: deadly nightshade (belladonna), mandrake


    - In ancient Greece, mandrake was used as an anaesthetic (or poison, in higher doses)

    - Witches smeared extracts on their armpits: avoided toxic oral route, got maximum hallucinogenic effect = felt like they were flying - Blocks certain acetylcholine receptors - Modern use: prevention of motion sickness (patches behind the ear)

    Natural Products 2: Medicines

    COCH3

    Salicin

    Acetyl-salicilic acid: aspirin

    - From Willow tree bark, which was used in folk remedies for treating fevers
    - Led to synthetic analogue, modern aspirin

    Natural Products 2: Medicines

    Ventolin Ephedrine
    - From Ephedra plants, basis of ancient Chinese herbal remedy Ma Huang (100 AD) for treating respiratory illness - Used clinically since 1926 as bronchodilator to treat asthma

    - Similar to adrenaline, but also stimulates heart (not good in a drug) - Stimulated research resulting in the non-stimulant drug Ventolin

    Natural Products 2: Medicines

    Quinine

    - Found exclusively in the bark of the Chinona tree - Used as a malaria treatment since 1600s - Now synthetic derivatives used, due to widespread resistance

    Natural Products 3: Stimulants

    Caffeine

    Nicotine

    - Caffeine-containing plant leaves + seeds have long been brewed to produce stimulant drinks - Such stimulants naturally act as feeding deterrents to repel insect herbivores that consume plants leaves - Tobacco plant can up its production of nicotine 4-fold when under attack by insects; nicotine by-products are used as insecticides

    Natural Products 3: Stimulants

    Cocaine
    - Coca leaves have been used as a source of cocaine for > 2,000 yrs - Used by Incas in religious ceremonies - Introduced to Europe by conquistadores - Leaves chewed daily by >8 million native peoples in the Andes, to alleviate feelings of hunger and fatigue - Inhibits re-uptake of excitatory neurotransmitter dopamine

    Natural Products 4: Halucinogens

    Morphine (= opium)

    Heroin (synthetic derivative)

    - Found in only 2 species of poppy flower (Papaver)

    - Milky exudate of seed capsules is 25% opiate - Used as a baby calming treatment in ancient Egypt - Binds to brain receptors for short peptides called enkephalins, derived from endorphins

    Natural Products 4: Halucinogens


    Similar spatial relationships of (*)-marked atoms responsible for similar pharmacological effects

    Enkephalin Morphine

    * *
    *

    Natural Products 4: Halucinogens

    Tetrahydrocannabinol

    Lysergic acid

    - Lysergic acid is the parent compound from which ergot alkaloids are derived, such as LSD - Produced by fungus; often affected stored grain in Middle Ages - Such compounds found in Aztec magical preparation ololuiqui - Structural mimics of human neurotransmitter 5-hydroxytryptamine

    Lysergic acid Diethylamine (LSD, synthetic)

    Secondary Metabolites
    - Produced from a small number of key intermediates, often generated as by-products of primary metabolism acetate (in the form of acetyl coA) mevalonate 4-carbon sugars - Perhaps arose as a means of dealing with excess metabolic intermediary compounds -2o metabolites then took on ecological roles as toxins, etc.

    Secondary Metabolites
    - Typically play ecological roles in nature, deterring would-be pests, predators or pathogens - Affect humans due to structural resemblance to innate neurotransmitters, or by binding to proteins in a way that disrupts normal cellular function - Natural products are the basis for a big % of pharmaceutical drugs currently on the market -

    Simple building blocks serve as the basis for each major pathway of secondary metabolism: (1) Shikimate Aromatics (ring - C3 chain)

    (2)

    Amino acids

    Alkaloids, Penicillins (N-containing) Terpenes, Steroids

    (3)

    Mevalonate

    (4)

    Acetate

    Polyketides (aromatics, macrocycles)

    (photosynthesis)

    Polysaccharides Glycosides Nucleic Acids

    phosphoenol pyruvate

    Shikimate pathway
    Shikimate Aromatic Compounds Lignans

    (1)

    pyruvate

    aromatic amino acids aliphatic amino acids


    CITRIC ACID CYCLE
    CH3COSCoA

    Alkaloids (2)
    Peptides Penicillins Cyclic Peptides

    acetyl CoA CH3COSCoA

    -O

    2CCH2COSCoA

    CH3COCH2COSCoA
    CH3COSCoA

    CH3COSCoA

    Isoprenoids (terpenes, steroids,

    mevalonate

    (3)

    carotenoids)

    (4)

    Polyketides, Fatty Acids

    Prostaglandins, Macrocyclic Antibiotics

    (1) Shikimate pathway


    from the Japanese flower shikimi (, Illicium anisatum) (A) Biosynthesis of aromatic amino acids (tyrosine, phenylalanine, and tryptophan) lead to alkaloids (B) Build aromatic secondary metabolites

    Shikimate
    Podophyllotoxin

    Shikimate biosynthesis
    Shikimate + PEP Chorismate

    Prephenate

    Other shikimate metabolites: ring-C3 ...ring-C2 ...ring-C1 Cinnamic acid - NH3

    + NH3

    Tyrosine, Phenylalanine

    Biosynthesis of phenyl compounds


    ring-C1 type

    vanillin

    vanillic acid

    salicin

    salicylic acid

    - In plants, many shikimate metabolites are allelopathic: they inhibit growth of competitors - Insoluble forms often linked to sugars in plant tissue - Soluble acidic forms leach out into surrounding soil in rain

    phenylalanine

    Lignans & Lignins


    Cinnamic acid

    Polymerization: complex lignins

    Enzymatic coupling: dimeric lignans Cinnamyl alcohol

    Podophyllotoxin

    Large % of woody plant biomass

    Podophyllotoxin
    - An important shikimate compound - Used by native Americans to cure warts - Powerful inhibitor of mitosis; found to block enzyme tubulin polymerase
    -

    Flavanoid Biosynthesis
    Shikimate + 3 acetates = flavanones

    Cause bitter tastes in plants, especially polymerized tannins; deter feeding by herbivores

    Derived compounds are responsible for much of plant color

    (2) Alkaloids
    (2) Amino acids Alkaloids, Peptides, Penicillins

    Penicillin

    Strychnine (alkaloid) Cyclosporin A (cyclic peptide)

    Alkaloid characteristics
    - Non-(normal)-peptide, non-nucleic acid compounds that contain nitrogen - Common in fungi, plants, insects + amphibians

    - Derived from amino acid precursors

    Tyramine

    Tyrosine Dopamine

    Mescaline - potent hallucinogen from the peyote cactus - competitively binds to dopamine receptors

    Penicillin Biosynthesis
    a-adipate + cysteine + valine

    - start with peptide made of 3 amino acids (including a non-standard a.a., a-adipate)

    a-adipate + cysteine + valine

    isopenicillin

    synthase

    penicillin N

    epimerase

    isopenicillin N

    cephalosporins

    penicillins

    Penicillins: Mechanism of Action


    This class of antibiotics interferes with synthesis of the cell wall of Gram-positive bacteria (Staphylococci, Streptococci) Cell wall is a repeating polymer of disaccharide, tetrapeptide repeats cross-linked into a 3D matrix (1) cleave here (transpeptidase) sugar - sugar - phospholipid
    L-ala

    D-glu L-lys D-ala D-ala (glycine)5 (2) cross-link here

    Penicillins: Mechanism of Action


    Penicillins inhibit the bacterial transpeptidase enzyme by mimicking its natural substrate, the terminal D-alaD-ala Transpeptidase attacks the b-lactam ring of penicillin, forms a covalent bond; enzyme is now out of business

    (1) NO CLASS next Monday (2) For NEXT WEDNESDAY - bring to class a small amount of some spice, seeds, leaves, fruit, or medicinal herb - pick something with a strong taste/smell, or that you know is used in a folk remedy - at Wednesdays lecture, you will put your material in a tube and label it; I will then add solvent and extract the natural products from it over the weekend - in the next lab, you will bioassay the extracts of your material for antibiotic activity and cytotoxicity

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