dietary -- glycogenolysis -- gluconeogenesis

1. absorptive phase

2. postabsorptive phase

3. early starvation

4. intermediate starvation

5. prolonged starvation

2 pyruvate -- 1 glucose

4 ATP and 2 GTP neded (6 nucleotide phosphate equivalents so ENERGY INTENSIVE)

any molecule that can be converted to pyruvate

ex) lactate and several amino acids, glycerol

Overcome the largely exergonic, irreversible steps of glycolysis

Pyruvate Carboxylase (ATP), Phosphoenolpyruvate carboxykinase (GTP), Fructose 1,6-bisphosphatase, glucose 6-phosphatase

Metabolically irreversible

Uses biotin as a cofactor 

Allosterically ACTIVATED by acetyl-CoA

Anaplerotic for TCA cycle (replenishes OAA from pyruvate)

Takes place in mitochondria

ATP cleaved in this reaction

Pyruvate reacts with bicarbonate

Synthesis of PEPCK increases during fasting

Takes place in cytosol

Converts OAA to PEP 

Molecule of GTP/ATP cleaved

Cofactor for Pyruvate Carboxylase

Binding site of carbonate ions

Has a carboxyl group and lysine residue

Can't leave mitochondria so converted to malate in MC and converted back to OAA in cytosol.

Then OAA is decarboxylated and phosphorylated by PEPCK

Metabolically irreversible

Allosterically inhibited by AMP and Fructose 2,6-bisphosphate (F2,6BP)

Converts fructose 1,6 bisphosphate to fructose 6-phosphate

Metabolically irreversible hydrolysis

Found only in liver,kidney, pancreas, and small intestine - only these tissues can serve as a source of glucose from gluconeogenesis

glucose-6-phosphate to glucose

Precursor for glycogen and glucose synthesis

Starting poing for pentose phosphate pathway

Glucose 6 phosphatase only present int sissues responsible for maintaining blood glucose levels, like the liver and kidney

In liver, glucose 6 phosphatase is highly regulated

1. Allosteric Control

2. Covalent Modifications

3. Substrate Cycles (futile)

4. Genetic Control - enzyme concentrations

Catalyzes formation of Fructose,2,6 bisphosphate (glycolysis) -- insulin

F26BP will allosterically activate PFK-1 to from fructose 1,6, bisphosphate

breaks down fructose 2,6 -bisphosphate to make fructose 6 phosphate. 

Active when phosphorylated, and will be stimulated by glucagon 

Regulateds PFK-1 and FBPase 1. NOt an intermediate

Allosterically activates PFK 1, and allosterically inhibits FBPase1

interaction of glycolysis and gluconeogenesis

Lactate from peripheral tisseus goes to liver and is made into glucose; glucose can go back to periphreal tissues

Liver uses lipids for energy

NADPH, Fatty Acids, cholesterol, nucleic acids

happens in mammary glands, liver, adrenal galnds, adipose

NOT IN BRAIN/MUSCLE

Produces 5 carbon sugar (ribulose 5-pohsphate) as well as production of NADPH

three molecules of a 6 carbon compound are converted into three molecules of a five carbon sugar with release of 3 mol CO2

Disposes excess pentose phosphates by converting them to glycolytic intermediates

Series of CC bond cleavage and fomration reactions

Ribulose 5-P --> Ribose 5P or Xylulose 5 P

2Xylulose 5-P + Ribose 5 P --> 2Fructose 6P + GAP

Transketolase and transaldolase have broad substrate specifities - catalyze exchange of 2 and 3 carbon fragments between sugar phosphates; for both enzymes, one substrate is an aldose and other is a ketose

Biosynthetic pathways - FA synthesis, chloesterol synthesis, steroid hormone synthesis)

Detoxifcation

Reduced glutathione as an antioxidant

Generation of superoxide radicals

GTP energy source for AMP

A TP energy source and NH3 soure for guanylate

Ribose phosphate pyrophosphokinase (PRPP synthetase) (ADP inhibits)

PRPP

Glutamine PRPP amidotransferase (AMP, GMP, IMP inhibit)

5-Phosphoribosylamine

Adenylosuccinate synthetase (inhibit by ATP)

IMP

aspartate, PRPP, carbamoyl phosphate

Ring made first and thena ttached to ribose-5-phosphate

Has three active sites

Substrate channeling limites diffusion

Channel is 100 A

Glutamine, ADP, ADP

Normal activity (no CTP) 

CTP inhibits ATCase, but ATP+CTP counters effect because prevents change in ATCase activity

(Aspartate trans carbonylase)

Ribonucleotide reductase converts ribose to deoxyribose - reduction involves replacement of 2'OH with H

Series of Redox reactions

acts on ribonucleotide dipohsphates

Has regulatory sites and allosteric effectors (R1 and R2 subunits) cysteines can be oxidized/reduced

provide a balanced pool of precursors for DNA synthesis

ATP stimulates on/off switch, dATP will have negative allosteric effect on enzyme

substrate specificty regulation - shows a balanced pool of all the different nucleotides

Both activity and substrate specificity regulated by effector binding

Enzyme activity: ATP activates, dATP inactivates

Substrate specificity: When ATP or dATP is bound, favors reduction of UDP and CDP. When dTTP or dGTP is bound, favors reduction of GDP or ADP

Urea 

Most mammals excrete in form of allantoin, allantoate by bony fishes

Gout

It's treated with allopurinol which inhibits xanthine oxidase. The oxypurinol generated is a strong competitive inhibitor of XO

Nucleotide biosynthetic pathways

ex) Glutamine, azaserine, acivicin

Series of redox reactions - nitrogen converted to 2 moles of ammonia - nitrogenase expends up to 16 ATP/N2

Dinitrogenase reductase will be part of the complex that uses ATP and drives the formation of ammonia from the N2 gas

Iron-molybdenum cofactor

Oxygen - leghemoglobin acts as an oxygen sponge by binding oxygen

Nitrogen incorporation into carbon skeletons catalyzed by glutamine synthetase

Assimilates ammonia into glutamate to yield glutamine

Has 12 identical subunits

1) Allosteric - all 8 molecules needed to block enzyme activity -- adjusts glutamine levels

2) Covalent - adenylation of tyrosine residue (inhibitory) done by adenylyltransferase, AT

Uridylylation of Tyrosine stimulates deadenylation which activates glutamine synthetase

Uridylylation happens @ P2 subunit of AT - urdiylated AT will stimulate deadenylylation

Glycolysis

TCA cycle 

Pentose Phosphate pathway

Glutamate (precursor)

Glutamine

Proline

Arginine

Serine (precursor)

Glycine

Cysteine

Aspartate (precursor)

Asparagine

Methionine

Threonine

Lysine

Alanine

Valine

Leurcine

Isoleucine

Tryptophan

Phenylalanine

Tyrosine

The source of the sulfur in cysteine is from adenosine-5-phosphosulfate (APS) and 3-phosphoadenosine 5-phosphosulfate (PAPS)

Their reduced sulfide ions incorporated into cysteine

Homocysteine is the precursor that is derived from methionine

Serine involved in this synthesis as well 

Precursor is oxaloacetate

10 Step synthesis

Aspartate-B-semialdehyde is a common intermediate for Lysine, Methionine, and Threonine biosynthesis

Precursor is Threonine to make isoleucine and valine

Valine will be converted to leucine

Phenylalanine, Tyrosine, Tryptophan

Phenylalanine precursor for tyrosine

intermediate in aromatic amino acid biosynthesis in bacteria, fungi, and plants

Carbon from erythrose 4 phosphate, carbon from PEP

5-phophoribosyl-1-pyrosphate (PRPP) intermediate 

(PRPP used in purine synthesis)

Prephenate

Animals can produce Tyrosine directly from phenylalanine via hydroxylatoin

Atoms of histidine are derived from PRPP, ATP, glutamine, & glutamate

Ribose-5-Phosphate is a precursor

bilrubin build up because of insufficient gluuronyl bilrubin transferase levels - can cause jaundice

Fluorescent light will cause bilrubin to form soluble products

Most are heterozygotes; acute intermittent porphyria: build up of delta aminolevulinate and porphoilinogen can result in abdominal pain and neurological dysfunctions

homozygous can cause anemia due to insufficient heme synthesis

Treatment: diet, IV, administration of heme/derivatives

Half of stored creatine originates from food

Endogenous synthesis is from liver and made from arginine and glycine

Hydrolysis of phosphocreatine important source of metabolic energy 

Leads to reducing intracellular environment

Glutamate, cysteine, & glycine are precursors 

Few disulfide bonds in intracellular proteins vs many in extracellular

Important in keeping SH groups (cysteins) and Fe (ferrous) in reduced state

amines, often highly bioactive -- (neurotransmitters, vasodilation)

auxins (indole 3-acetate) derived from plants from tryptophan

Gaseous biological messenger

Diffuses through cell membrane
Arginine is the precursor

Diffusion: short distance of activity - neurotransmission, blood clotting, pressure control  

In many aminotransferase reactions, alpha-ketoglutarate is the amino group acceptor

All aminotransferases have pyridoxal phosphate (PLP) as cofactor 

Ammonia - aquatic vertebrates, bony fishes, amphibia

Urea: terrestrial vertebrates, shark

Uric acid: birds, reptiles

Alanine is carrier of ammonia and carbon skeleton of pyruvate from skeletal muscle to liver

Pyruvate produced by deamination of alanine (liver) is converted to glucose (back to muscle)

Ammonia is excreted