1.8 – Lipid Signaling: Synthesis of Triglycerides:  Start out with glycerol, phosphorylate it on Carbon 3 Add 2 fatty acids to carbon 1 and 2 (activated by being attached to coA)  Remove phosphate group  2 fates: o Remain as a diglycerideo You can add another fatty acid to carbon 3 and make a triglyceride (requires energy and overall 3 acyl co A) Synthesis of Phospholipids:  To activate the head group (ex: choline):o ATP is used to phosphorylate ito & a molecule called CTP further activates it o Now you have a VERY activated choline 2 fates: o Can remain as a diglycerideo Move onto to make a phospholipidPhospholipases & Signaling: » Phospholipases catabolize phospholipids » Phospholipase A1: cleaves ester bond on carbon 1 (C-O)» Phospholipase A2: cleaves ester bond on carbon 2 (C-O)» This releases fatty acid» Phospholipase C: cleaves part of the head group » Phospholipase D: removes head group PLC & PIP2 Gives IP3 & DAG: PLC acts on PIP2 by cleaving it into the head group (IP3) and diglycerol (DAG)  PLC makes 2nd messengers: o IP3 will move into cell to open up channels (2nd messenger)o The remainder of the molecule (diglyceride) acts as a 2nd messager by activating protein kinase C PLA2 Generates Eicosanoids: Extremely potent arachidonate (20:4beta6) metabolites Extremely short lived Extremely small amounts  Not like true hormones:o Act locally where they are made, not transported in bloodo Act immediately, then destroyed, not stored/released Wide range of physiological responses: Vasoconstriction/vasodilation Platelet aggregation/inhibition Smooth muscle contraction/relaxation Involved in:o Inflammationo Fevero Paino Blood clottingEicosanoid Biosynthesis:o PLA2 leads to potent local hormones (eicosanoid) that come from AA (arachidonic acid) o This AA can lead to leukotrienes o Or: cyclooxygenase will lead to prostaglandins ad thromboxanes o Specific species produced based on enzymes present in the cell Aspirin: 2.1 – Nucleotides & 1-C Metabolism: Nucleotides: nitrogenous base (GCATU), phosphate, 5-carbon sugar (ribose) from the PPP1-Carbon Metabolism in Health & Disease:» Many reactions in metabolism involve the enzymatic transfer of “1-carbon” groups between molecules» These 1-carbon groups are carried by four coenzymes:o Tetrahydrofolate (THF)o S-adenosyl-methionine (SAM)o Biotino Vitamin B12 » B-vitamins give us THF, biotin, and B12» THF and B12 gives us SAM*Amino acids can provide 1-carbon units, which are attached to enzymes fornucleotide synthesisFolate is a vitamin essential to good health:- It is inactive…- So: it must be reduced to its active form, THF, by the enzyme dihydrofolate reductase- Folic Acid (from diet)  dihydrofolate  tetrahydrofolate (more reduced)- ^All done by dihydrofolate reductase: o makes THF from folateo converts DHF back to the THF during nucleotide biosynthesiso important target for chemotherapy - Tetrahydrofolate is important for amino acid, purine, and thymidine synthesis  It collects 1-carbon units from amino acid catabolism and transfers them to other biosynthetic pathways SAM: an important methyl group donor  THF-CH3 is required for methylation of B12  Then homocysteine accepts methyl group from B12 and it is converted to methionine  Methionine  SAM (thanks to ATP) Adenosine is releasedToo much homocysteine is BAD:o Increases risk of heart attacks, stroke, birth defectso You want to avoid B12 or Folate deficiency so that there isn’t accumulation of homocysteine RDAs and Sources of Folate and Vitamin B12: Folate: especially important for women who could get pregnant Folate deficiency: causes neural birth defects very early, before you know you’re pregnant Sources of Folate: red meat, green leafy vegetables, fruits, liver, kidney  Vitamin B12: meat, eggs, dairy products, fishIntroduction to Nucleotides: ATP, an adenine nucleotide, is the energy currency of the cell Adenine nucleotides are components of 3 major coenzymes = NAD, FAD, CoA Important metabolic regulator (cAMP) Nucleotides carry activated intermediates in many biosynthetic reactions (UDP-glucose, CDP-choline) They are building blocks for DNA & RNA  Synthesis of nucleotides is the target of many chemotherapeutic agents (treating cancers) Disorders of nucleotide degradation are common and cause major health problems Nucleotides are building blocks of nucleic acids (RNA & DNA)» RNA is a polymer of 4 nucleotides (GTP, CTP, ATP, UTP)» DNA is a polymer of 4 nucleotides (dGTP, dCTP, dATP, dTTP)» ATP: energy currency of the cell, part of vital coenzymes, cAMP production» GTP: “G-proteins” the p in GTP is needed for protein synthesis» CTP: involved in lipid biosynthesis» UTP: involved in polysaccharide biosynthesis Nitrogeneous Bases: either purine or pyrimideDouble ring = purine Single ring = pyrimidine - G = guanine- C = cytosine- A = adenine- T = thymine- U = uracilNomenclature: NucleoSIDE = base and the sugarNucleoSIDE-phosphates: refers to phosphate groupNucleoTIDE: includes the base, sugar, and P Aka… nucleosides are nucleotides without the phosphate.URACIL is in RNATHYMINE is in DNADNA is a polymer of nucleotides: - Structure: individual nucleotide monomers are linked (condensation) between OH on ribose and phosphate group of other monomer - This forms a phosphodiester link 2.2 – Nucleotide Biosynthesis: De Novo Nucleotide Biosynthesis: making nucleotides from scratch! All living cells synthesize nucleotides Use parts of small molecules (mostly amino acids) to synthesize precursoro Purineso Pyrimidines Use these common precursors to make other ribonucleotides Use a single enzyme to convert ribonucleotides to deoxyribonucleotides as needed for DNA synthesis Regulate activity of key enzymes to coordinate & control synthesis Purine Nucleotide Biosynthesis:» The PPP gives us Ribose-P» The ribose must be (very) activated with another 2 phosphate groups – PRPP » The step that commits us to PURINE biosynthesis is when amidotransferase adds NH2 from glutamine to the PRPP» We now have the precursor: IMP » Phosphates are added by kinases until we have ATP and GTP Many different ingredients are required to assemble the ring structure of purine bases:o Sources: Glutamine (gives us nitrogen), Aspartate, Serine via THF, Glycine, HCO3- o The involvement of THF (1-C carrier) is important Regulation of De Novo Purine Biosynthesis: