NATURAL PRODUCTS

NATURAL PRODUCTS Compounds that occur naturally in plants and animals Ubiquitous compounds are usually not classified as natural products. Ubiquitous = occurs everywhere in nature, universal excludes amino acids, nucleic acids, all compounds found in major metabolic pathways. Natural products are unique to only one species or family of organisms.

PRIMARY AND SECONDARY METABOLISM

A TYPICAL PLANT hn Glycolysis ENERGY Photosynthesis CO2 Respiration (daytime) CO2 Respiration H2O (nighttime) O2 N2 bacteria “N” TRACE METALS Na, Ca, K, Mg Fe, Cu, Co, Mo NO2-/NO3-/NH4+ H2O

PRIMARY METABOLISM Primary metabolism comprises the chemical processes that every plant must carry out every day in order to survive and reproduce its line. Photosynthesis Glycolysis Citric Acid Cycle Synthesis of amino acids Transamination Synthesis of proteins and enzymes Synthesis of coenzymes Synthesis of structural materials Duplication of genetic material Reproduction of cells (growth) Absorption of nutrients

SECONDARY METABOLISM Secondary metabolism comprises the chemical processes that are unique to a given plant, and are not universal. Secondary metabolism is the chemistry that leads to the formation of a natural product. Sometimes portions of this chemistry are common to a number of different plants or plant families, but the actual chemical produced (natural product) is usually different in one plant than in another. Common chemical precursors can lead to different results. Secondary metabolites (in most cases) do not appear to be necessary to the survival of the plant, but they may give it a competitive advantage.

Three Principal Groups of Secondary Metabolites Terpenes Lipid synthesized from acetyl CoA or from basic intermediates of glycolysis Phenolic compounds Aromatic substances formed via the shikimic acid pathway or the malonic acid pathway Nitrogen containing secondary products (alkaloids) Alkaloids which are synthesized primary from amino acids

CO2 + H2O PRIMARY METABOLISM Photosynthesis Glucose Carbohydrates hn PRIMARY METABOLISM Photosynthesis Glucose Carbohydrates SECONDARY METABOLISM SECONDARY METABOLISM G L Y C O L Y S I S Building Blocks Phenyl- propanoids Amno Acids Fatty Acids Lipids Flavonoids Proteins Alkaloids synthesis enzymes Acetyl CoA regulation Acetogenins Terpenes Steroids Nucleic Acids Citric Acid Cycle reproduction RNA DNA CO2 + H2O + ATP

Glucose hn CO2 photosynthesis starch n glycolysis polyketides (6 carbons) hn CO2 photosynthesis starch n glycolysis polyketides acetogenins erythrose- 4-phosphate lipids fatty acids phosphoenol pyruvate (PEP) (3 carbons) shikimic acid anthanilic acid acetyl- coenzymeA (2 carbons) mevalonic acid phenylpropanes lysine ornithine oxalo- acetate citric acid cycle phenylalanine tyrosine energy (ATP) + CO2 + H2O tryptophan terpenes steroids carotenoids NH3 nicotinic acid aspartic acid alkaloids glutamic acid

Terpene functions Growth and development carotenoid pigments are tetraterpenes chlorophyll side chain is diterpene giberellins (hormones) are diterpenes abscissic acid (hormone) is a sesquiterpene C15 sterols are triterpenes

Terpenes that act against vertebrate herbivores Triterpenes 1. Cardenolides (glycosides) - acutely toxic influence Na+/K+ ATPase of heart muscle medicinal application - digitalis (from foxglove), used to treat heart disease. Can slow and strengthen heart beat 2. Saponins (soaplike) - steroid, triterpenes glycosides have lipid and water soluble parts of molecule toxicity related to sterol binding, membrane disruption

Terpenes as human medicinal drugs Limonene - monoterpenoid (C10) dietary anticarcinogen Artemisnin - sesquiterpenoid (C15) antimalarial Taxol - diterpenoid anticancer drug from Pacific yew (Taxus brevifolia)

Phenolics Plants produce a variety of compounds that contain one or more phenol groups - called phenolics Thousands of phenolics occur in plants

Phenolic Compounds Secondary metabolites which contain a hydroxyl functional group on an aromatic ring They are heterogenous group: Some are water soluble only in organic solvents Some are water soluble carboxylic acids and glycosides Some are insoluble polymer Many serves as defense compounds against herbivores and pathogens Other function in attracting pollinators and fruit dispensers

Types of Phenolic Compounds Benzoic acid derivatives Caffeic acid and other simple phenylpropanoids Flavones Isiplavones (Isoplavonoids) Flavonoids Lignin

N-containing secondary compounds Those are encountered less commonly in plants than the phenolics and terpenoids Those are important in view of their bioactivity as drugs and toxins They are synthesized from aliphatic and aromatic amino acids Aliphatics via TCA cycle Aromatics via shikimic acid pathway

WHAT IS AN ALKALOID ? Naturally-occurring compounds that contain nitrogen Many have heterocyclic rings as a part of their structure They are found mostly in plants Many are physiologically active (often spectacularly) Many are used by native peoples for religious or medicinal purposes. Many are basic (“alkaline”, due to an unshared pair on N) Those nitrogen compounds that are found in all organisms (i.e., amino acids, nucleic acids, etc.) are not considered alkaloids. Alkaloids are “secondary metabolites”, they are not involved in primary metabolism.

How are Phytoalexins Formed? The “-noids” Shikimic acid pathway (phenylpropanoids) Hydroxycinnamic acids Coumarins Hydroxybenzoic acids Mevalonic acid pathway (Isoprenoids) Carotenoids Terpenoids Combination of Pathways Shikimic-Polymalonic) Flavonoids and anthocyanins

TEXTS: Manfred Hesse, Alkaloids - Nature’s Curse or Blessing?, Wiley-VCH (2002). (on reserve) R.E. Schultes, A. Hofmann and C. Ratsch, Plants of the Gods, 2nd ed., Healing Arts Press (2001). (bookstore) D. Pavia, Chemistry of Natural Products - Notes, WWU Chemistry Department (online) See web site for reserve book list GRADING: Two Hour Exams, occasional quizzes, Problem sets, Poster Presentation