Amino acids, DNA and Cholesterol
Essential Amino Acids
Lys, ISO, LEU, THR, VAL, TRY, PHE, MET, HIS, ARG
Required in diet; no exception
“Little TV Tonight (PM) – HA”
Nonessentials
Serine → Gly or Cys (from Homocysteine + Ser)
Glutamate → Gln, Pro, Arg
-His req. for the syn of Glu
One Carbon Metabolism
All begins with Folate; Folate to FH4 via Dihydrofolate reductase (2x)
Formate, His, Ser, Gly, Formaldehyde, Methylene-FH4 can all donate carbons
B12 cofactor required for Methylmalonyl CoA conversion to Succinyl CoA
-it also binds to IF to allow absorption in Ileum and transport via transcobalamins
-stored in liver (3 year supply)
Met is not a major product of SAM cycle because it can never be produced in enough quant.
Purpose of cycle is to produce C1 pool (via SAM) to produce products below)
SAM req for the mormation of Epinephrine, Creatine, Methylated nucleotides, Phosphatidylcholine and melatonin
Methotrexate and 5-FU inhibit dihydrofolate reductase and thymidylate synthetase, respectively; interrupting dUMP conversion to dTMP → deprives cells of C1 pool
Purines and Pyrimidines
PRPP is precursor to both purines and pyrimidines
Ribose is reduced to Deoxyribose via Ribonucleotide reductase (which is reconverted via Thioredoxin reductase)
Ribonecleotide reductase forms disulfide bond that requires cleavage
Purines are built on PRPP ring that gains an amino group from Gln [start with sugar, build ring]
This first step is regulated by negative inhibition of IMP, AMP and GMP
Nitrogen sources for Purine base from Glycine, Metheny-FH4 and Glutamine amide
Purines are degradated via Xanthine to form Uric acid. This step is inhibited by Allopurinol.
Jacked up Purine metabolism may present clinically as Gout
Pyrimidine Bases start with Gln + CO2 + 2 ATP; secondary Nitrogen source from Aspartate
First step forms Carbamoyl phosphate (CAP – very similar to Urea Cycle)
This step is inhibited by UTP
Pyrimidine Phosphoribosyl transferase is responsible for salvage of pyrimidines
Comparison of Carbamoyl Phosphate Synthetases
CPSI CPSII
Pathway Urea Cycle Pyrimidine biosynthesis
Source of Nitrogen NH4+ Glutamine
Location Mitochondria Cytosol
Activator N-Acetylglutamate PRPP
Inhibitor – UTP
Special Amino Acid Products
Glutamate → GABA
Arginine → Citrulline (giving off NO as a signaling molecule that activates vasodilation via cGMP cascade)
Tryptophan → Serotonin → Melatonin
Phenylalanine → DOPA → Melanin
 |
Typrosine→ DOPA → Dopamine → Norepinephrine → Epinephrine
Methylated and oxidized derivates of Nor and Epi → Vanillymlandelic Acid (VMA), which is found in urine as end product of catecholine processing
Lipid Byproducts
Linoleic (18:2D9,12) and Linolenic (18:3D9,12,15) are essential Fatty Acids
Arachidonic acid forms the Eicosanoids
Phospholipids (mainly glycerol-3-P based plus sphingomyelin)
Arachidonic Acid, Leukotrienes and Prostaglandins are derivatives of Phospholipids
Serum lipoprotein structural component
Regulators of enzyme function
|
Phosphatidylcholine and Phosphatidylethanolamine are neutral compounds (Zwitterionic)
SAM to SAH is most important steop; pathway of maintaining PCH and PETH wastes Serine
Phosphatidylglycerol is anionic compound; forms Cardiolipin (which comprises 15% of mito membrane)
Phosphatidylinositol synthesis occurs in ER
Phospholipases: PIP2 → IP3 (Ca++ homeostasis) + Diacylglycerol (Cell Division control)
Prostaglandins are for protection via clotting, edema, inflammation, erythema; prostaglandin formation is inhibited by NSAIDS
Eicosanoids – Homorne like function; produced/degraded in target tissue
Leukotreines – from arachidonic acid; have 3 conjugated DB
functions of glutathionine derivatives, vascular permeability, leukocyte proliferation
bronchoconstriction
Sphingolipids/Glycolipids (Cermide based)
Essential in membrane bilayer
Signal transduction molecule (cell metabolism, apoptosis & ABO blood group signaling)
Hydrophobic Palmitoyl CoA + Hydrophilic Serine → Ceramide
Ceramide → Sphingomyelin and Cerebroside/Ganglioside products
Gangliosides builds up in breakdown pathway [lots of lysosomal storage diseases]
Glycolipids: Very antigenic: blood groups and signals during devo
Cell-Cell interaction and recognition
Steroid-based lipids
Cholesterol
Steroid Hormones
Bile Salts
Cholesterol
Steroid, tetraring structure, flexible 8 carbon tail, single -OH group at C3 and a D5,6 Double Bond
Is extremely hydrophobic
Modulation of membrane fluidity, precursor for bile salts, steroid hormones and VitD
C/CE are transported in blood lipoprtoteins
In the liver, bile salts are formed from C by hydroxylation of the sterol ring, oxidation of side chain and conjugation of the carboxylic acid group with Glycine or taurine
The sterol ring cannot be degraded. It is excreted intact, mainly as unresorbed bile salts
Formed from Acetyl CoA and Acetoacetyl CoA → HMG-CoA
-Involves cytochrones P450; bound to ER
Adenylate Cyclase
 |
Ø 2 N-linked B-adrenergic extracellular binding units, 7 transmembrane helices → GDP cleavage, GTP-a activation
Ø cAMP is the 2nd messenger, formed from ATP Ø Hydrolysis of the GTP by the a subunit returns the subunit to its original conformation, causing dissociation Ø cAMP binding to regulatory chains activates PKA phosphorylation of SER/THR residues Ø Gs has intrinsic GTPase activity Ø Cholera toxin is an enzyme that catalyzes the transfer of ADP ribose from intracellular NAD+ to as (Gs alpha chain) |
cAMP induced targeting
| Target Tissue | Hormone | Major Response |
| Thyroid | TSH | T3/T4 synthesis and secretion |
| Adrenal Cortex | ACTH | Cortisol Secretion |
| Ovary | LH | Progesterone Secretion |
| Muscle | Adrenaline/Epinephrine | Glycogen Breakdown |
| Bone | Parathormone | Bone Resorption |
| Heart | Adrenaline/Epi | ↑ HR and Contractile Force |
| Liver | Glucagon | Glycogen breakdown |
| Kidney | Vasopressin | H2O resorption |
| Fat | Epi, ACTH, Glucagon, TSH | Triglyceride breakdown |
Tags: Amino acids, Cholesterol, DNA
