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Lecture 40 Amino Acids 2 Amino Acid Biosynthesis Nitrogen Fixation Amino Acids as Precursors Key Concepts • Amino acid biosynthesis • Herbicides and RoundUp Ready soybeans • Nitrogen fixation in the biosphere • Amino acids are precursors of numerous biomolecules Amino acid biosynthesis Atmospheric nitrogen is reduced to ammonia (N2 ---> NH3) primarily by microorganisms that live in the soil and are associated with plant roots. Humans need to obtain 9 of the 20 amino acids from their diet because we lack the necessary enzymes for de novo biosynthesis. There are at least 20 different pathways to specify the synthesis of all 20 amino acids. Most, but not all, of these pathways are present in humans. Some essential amino acids obtained in the diet provide substrates for other amino acid biosynthetic pathways. One example of this is the conversion of phenylalanine (essential amino acid) to tyrosine (non-essential amino acid) by the enzyme phenylalanine hydroxylase. Tyrosine is not only an amino acid required for protein synthesis, but also a precursor for neurotransmitter synthesis (DOPA) and skin pigments (melanins). The enzyme tyrosinase is required for melanin synthesis. Biosynthetic pathways found in plants are responsible for the production of amino acids that are "essential" to humans. (Similar pathways are found in bacteria). Where does this come from? Where do these come from? Biosynthetic pathways found in plants are responsible for the production of amino acids that are "essential" to humans. (Similar pathways are found in bacteria). Where do these come from? Where do these come from? Which human enzyme is required to keep tyrosine off of the Essential Amino Acid list (i.e., how do humans make tyrosine?). The most common form of albinism is due to a deficiency in the enzyme tyrosinase. Would a diet rich in the amino acid tyrosine be an effective treatment for albinism? Explain. Why aren't individuals with the disease phenylketonuria (PKU) also albinos considering that they have a deficiency in phenylalanine hydroxylase, the enzyme required to convert phenylalanine to tyrosine? Do individuals with PKU entirely lack proteins containing the amino acid phenylalanine? Explain. Herbicides and RoundUp Ready Soybeans De novo synthesis of aromatic amino acids (phenylalanine, tryptophan, tyrosine) in plants and bacteria requires the Shikimate Pathway. A key enzyme in this pathway (EPSP synthase) is the target of the herbicide glyphosate, also known as Round-Up. Genetically engineered crop plants such as soybeans have been developed that are resistant to glyphosate to permit herbicide application directly to fields. The use of these "Round-Up Ready" crops is controversial for a number of reasons. In fact, use of genetically modified organisms (GMOs), including plants, is a hot topic both in the USA and internationally. If cows ate Round-Up Ready alfalfa that was recently sprayed with the herbicide glyphosate, would they get sick? Explain. Phenoxy-based herbicides such as 2,4-D are used on golf courses to control broadleaf weeds that can grow within the turf grass. Do you think that 2,4-D kills "weeds" but not grass by inhibiting the Shikimate pathway? Explain. Plants and most bacteria contain all the enzymes required for de novo synthesis of amino acids, yet vertebrates synthesize only half of the 20 amino acids. What might explain this observation? Nitrogen fixation in the biosphere The nitrogen in amino acids, nucleotides and other biomolecules ultimately comes from atmospheric nitrogen. Conversion of N2 → NH3 is carried out by bacteria and blue-green algae. Note that the pKa of NH3 is 9.2 so at physiological pH (~7), ammonia exists as an ammonium ion NH4+ All organisms can use ammonia (NH3) in metabolic pathways to synthesis amino acids, nucleotides and porphyrins, but only bacteria and blue-green algae can fix atmospheric nitrogen into NH3. The best studied nitrogen-fixing soil bacteria is Rhizobium which invades the roots of leguminous plants such as soybean and saguaro cacti. Why are the nodules red? The Nitrogen Fixing Enzyme Buchanon et al., Fig. 16.6 The biological process requires a complex enzymatic reaction involving multiple redox centers. The two primary enzymatic activities are the reductase and the nitrogenase. Nitrogenases contain an iron-sulfur (Fe4S4) cluster for redox reactions Nitrogen fixation is very costly with 16 ATP being hydrolyzed for each N2 that is reduced. N2 + 8 e- + 16 ATP + 16 H2O → 2 NH3 + H2 + 16 ADP + 16 Pi + 8 H+ Many desert plants are legumes, for example palo verde trees. What might be the evolutionary advantage of this for palo verde trees? Why do organic farmers rotate soybean crops through their planting fields? Amino acids are precursors of numerous biomolecules A variety of biomolecules are derived from amino acids including nucleotide bases, sphingosine, histamine, a potent vasodilator, the hormones thryoxine and epinephrine, the pigment melanin, the neurotransmitter serotonin, and the nicotinamide ring of NADH. Two other important biomolecules are nitric oxide, a first messenger signaling molecule that is derived from arginine, and the porphyrin ring of hemes which is derived from reactions utilizing glycine as the source of nitrogen and for some of the carbon atoms (other carbon atoms come from acetate). The first step in the biosynthesis of porphyrins in mammals is the condensation of glycine and succinyl CoA to form δ-aminolevulinate. Two molecules of δ-aminolevulinate condense to form porphobilinogen which is the precursor to heme ring synthesis. Genetic defects in porphyrin metabolism have been identified. The most notable disease of this type is congenital erythropoietic porphyria which causes urine to turn red, the skin to become light sensitive and teeth to glow in the dark (red fluorescent teeth). Moreover, red blood cells are short-lived due to very low levels of heme and patients are anemic. One way people treated anemia in the middle ages was to drink blood. The known cause of erythropoietic porphyria is lack of the enzyme uroporphyrinogen III cosynthase which leads to a buildup of the symmetric (but physiological inert) intermediate uroporphyrinogen I. This compound absorbs UV light. Could it be that erythropoietic porphyria is the biochemical explanation for the Vampire legend … drinks blood, sensitive to light, fluorescent teeth. It does make a good biochemistry story, but perhaps a bit of a stretch. Since erythropoietic porphyria is a form of anemia, and drinking animal blood was a common treatment for anemic symptoms (although it won't cure porphyria because dietary heme cannot enter red blood cells), it wouldn't be a surprise if someone with the disease was in fact labeled a vampire by the villagers (hard to miss the fluorescent teeth). In 1897 an Irish writer by the name of Bram Stoker published a book called "Dracula" that has served as the Vampire Guidebook. It is thought that Stoker's story, which is based in Transylvania, is loosely tied to Vlad III Dracula, aka Vlad Tepes, aka Vlad the Impaler, who lived in Transylvania in the 15th century. Our good buddy Vlad Tepes Bram Stoker Vlad Tepes’ father was known as Vlad Dracul, or Vlad the Dragon “Dracul” means dragon and devil in Romanian. Dracula, with the “a” on the end, means son of Dracul. So, Vlad Dracula was the son of the dragon or the son of the devil. He ruled much of what is now modern day Romania with an iron fist. If any village or town opposed him in his conquests, he would take half of the adults and impale them on stakes set in a large circle. He would then have a banquet in the middle of the circle, forcing the rest of the villagers to watch. His reputation spread quickly. Very effective crowd control, don’t you think? No one knows if he drank the blood of the impaled. Dracula’s Childhood Home Sighisoara, Transylvania, Romania Copyright © 2003 David R. Gang Copyright © 2003 David R. Gang Stoker set Dracula’s “Castle” in the Tihutsa Pass, in Eastern Transylvania, Romania This is what the real pass looks like. Not the Craggy Rocky Desolate Place that the movies lead you to believe, is it! Copyright © 2003 David R. Gang The only Dracula’s “Castle” you find in the Tihutsa Pass is this Hotel Dracula’s “Castle” in Bran Transylvania, Romania Transylvania, Romania Copyright © 2003 David R. Gang Copyright © 2003 David R. Gang The rooms all have Dracula themes Blood red satin sheets, black curtains, stuff like that. This place claims to be Dracula’s Castle, but Vlad probably only stayed a few nights here. It belonged to someone else. He never lived here. Great touristy place. If you want to see a truly great “Dracula” movie… Check out Werner Herzog’s 1979 film: Nosferatu, Phantom Der Nacht Starring: Klaus Kinski as Dracula, Isabella Adjani as Lucy Harker, and Bruno Ganz as Jonathan Harker. This is a creepy, eerie, make your skin crawl movie without the gore of most Vampire movies. Also has significant political statements about the Communist Regimes of Eastern Europe and Government in general. Black Plague as a metaphor And the rats …