Chorismate is an important precursor for aromatic amino acids

1. Chorismate is an important precursor for aromatic amino acids • Derived from PEP and erythrose 4-phosphate • First branch point of pathways, one leading to tryptophan, another to phenylalanine and tyrosine

2. Tryptophan biosynthesis requires PRPP, glutamineand serine

3. Tryptophan synthase has separable activities • Has an a2b2 structure • These distinct subunits (a and b) catalyze different portions of overall reaction • First reaction (a subunit) generates glyceraldehyde 3-phosphate • Second reaction (b subunit) involves PLP • Presents another example of substrate channeling (p. 540)

4. Tryptophan synthase reaction

5. Phenylalanine and tyrosine share prephenate as a common intermediate

6. Animals produce tyrosine from phenylalanine • Use an enzyme phenylalanine hydroxylase, which also participates in phenylalanine catabolism, lack of this enzyme causes phenylketonuria…more on that later

7. Lastly - Histidine biosynthesis • Histidine is derived from three precursors • PRPP contributes five carbons • Purine ring of ATP contributes nitrogen and a carbon • Glutamine supplies the second nitrogen • This pathway produces AICAR, a precursor in purine biosynthesis

9. Orchestrating the regulation of amino acid biosynthesis • No surprise – Feedback inhibition • For example:

10. However, remember it can be more complex • Concerted inhibition of glutamine synthetase • Also, do not observe a equal frequency of amino acids in proteins – must make proportional amounts to be efficient • Pathways can be organized into hierarchical clusters

11. Add parallelism through Isozymes Can modulate flux Sequential feedback inhibition

12. Intermediary metabolism  Amino acids  more biomolecules • Glycine and succinyl-CoA Are precursors for porphyrins

13. Glutathione, a redox buffer

14. Aromatic amino acids are precursors for several biologically significant compounds • Lignin – abundant plant polymer derived from tyrosine and phenyl- alanine • Plant growth hormone – auxin

15. Including neurotransmitters • All require PLP • decarboxylation Know the origin of compounds in fig 22-29

16. Another neurotransmitter, NO • And finally, back to nucleotides (in the book that is)

17. Amino acid catabolism • Account for 10-15% of human body energy production (primary pathways are glycolysis and fatty acid oxidation) • The twenty catabolic cycles converge to form five products, all entering the citric acid cycle • Chapter 18

19. Cofactors of amino acid catabolism • Know importance of H4folate, be able to recognize SAM (adoMet) and know its importance

20. Tetrahydrofolate • Intracellular carrier of methyl groups (can also can carry a methylene, or a formimino, formyl or methenyl; different oxidative states (fig 18-16) • Major source of these one carbon units is serine • Although versatile, most methyl group transfers are performed by adoMet

21. AdoMet • Synthesized from ATP and methionine • Displacement of triphosphates only observed in one other known reaction involved in coenzyme B12 synthesis

22. Acetyl-CoA is derived from several (ten) amino acids • Pyruvate can be a common intermediate

23. Glycine has an alternative fate • In addition to being converted to serine, and then acetyl-CoA, Glycine can be oxidized to form ammonia, carbon dioxide and a methylene group, which is transferred to tetrahydrofolate • Primarily an animal pathway • Also can form oxalate

25. Acetyl CoA is also a product of other amino acid catabolism • Portions of tryptophan, lysine, phenylalanine, tyrosine, leucine and isoleucine generate acetyl-CoA or Acetoacetyl CoA or both.

27. Disease from deficiencies in phenylalanine and tyrosine metabolism

28. Loss of phenylalanine hydroxylase leads to another pathway