Download Objectives 12

Storage of glucose (glycogenesis)
Glycogen synthesis (glycogenesis)
- liver, kidney store glycogen to replenish blood glucose (during food deprivation) for use by
brain and RBCs
- Muscle stores glycogen for needs of individual cells
- glycogen’s highly branched structure excludes water to decrease a tissue osmotic effect and
increases its efficiency as a substrate for glycogen phosphorylase, which removes glucose units
from the ends of branches
- glycogen synthesized from glucose
- glucose phosphorylated in glycolysis by glucokinase (liver) or hexokinase (muscle, kidney)
 glucose-6-P (ATP used)
- in muscle and heart  produce glycogen from lactate; these tissues have all enzymes for
gluconeogenesis except glucose-6-phosphatase (no free glucose produced)
- glucose-6-P  glucose-1-P by phosphoglucomutase
- glucsose-1-P (glucose residue to be added to growing glycogen molecule) is activated
chemically by attachment to UMP (derived from UTP)  forms UDP-glucose; reaction
catalyzed by glucose-1-P uridyltransferase; UTP used, 2 PPi removed  UMP, but UDPglucose has 2 phosphates  the other one is from the glucose-1-P; highly exergonic
- UDP-glucose serves as substrate for glycogen synthase; glycogen synthase regulated by
covalent modification (phosphorylation) in response to hormonal signals, and by allosteric
activation
1. Mobilization of glucose (glycogenolysis)
Glycogen degradation (glycogenolysis)
- principal enzyme is glycogen phosphorylase  hydrolysis of glucose residues from ends of
branches and phosphorylation of these residues
- enzyme contains binding sites for its substrates (glycogen, Pi), a cofactor (pyridoxal
phosphate), an allosteric activator (AMP), and allosteric inhibitors (ATP, glucose, glucose6-P)
-enzyme can be activated by phosphorylation in response to hormonal signals; phosphorylated
“a” form and dephosphorylated “b” form
- debranching enzyme and transferase move final four residues of branch to the end of a
chain so they can be removed by glycogen phosphorylase
- Glucose-1-P  glucose-6-P by phosphoglucomutase
- in liver, glucose-6-P dephosphorylated to glucose via glucose-6-Pase (last enzyme of
gluconeogenesis); glucose exported to blood
- in liver, glucose-6-P from glycogen, during postabsorptive phase of food deprivation, is not
metabolized via glycolysis; pathway inhibited by absence of fructose-2,6-BP  inhibition of
PFK-1; caused by glucagon  FBPase-2 active  less fructose-2,6-BP  increase FBPase-1
and decrease PFK-1
- muscle lacks glucose-6-Pase  cannot synthesize glucose; instead breakdown of glycogen
(via glycogen phosphorylase) provides energy by feeding glucose-6-P into glycolysis 
pyruvate  anaerobic LDH  lactate or pyruvate  Acetyl CoA via PDH  CO2 via citric
acid cycle
2. Synthesis of glucose (gluconeogenesis)
- synthesis of carbohydrate from noncarbohydrate precursors
- uses reaction in both mitochondria and cytoplasm
- gluconeogenesis occurs largely in liver; kidney makes some contribution during starvation; in
kidney glutamine released from muscle is primary gluconeogenic precursor
- starvation  liver glycogen depleted  gluconeogenesis essential for maintaining blood
glucose homeostasis
- muscle uses pathway for conversion of lactate to glycogen instead of lactate to glucose
Pyruvate carboxylase: Pyruvate  oxaloacetate (ATP + HCO-3  ADP + Pi, biotin cofactor)
- like other carboxylases  requires biotin as a prosthetic group to carry CO2, and requires
ATP to drive the reaction
- direct energy utilization for gluconeogenesis
- glucose has 6 carbons so two molecules of ATP used for each molecule of glucose synthesized
from pyruvate
- reactions only for those precursors that must be converted to glucose via pyruvate (lactate,
alanine, other amino acids)
Phosphoenolpyruvate carboxykinase- PEPCK: oxaloacetate  phosphoenolpyruvate (GTP
GDP + HCO-3)
- rate-determining and committed step of gluconeogenesis
- utilizes GTP as an energy source; 2 molecules of substrate consumed for each molecule of
glucose synthesized
- any precursors converted to one of citric acid cycle intermediates (oxaloacetate, fumarate,
succinyl CoA, alpha-ketoglutarate) use PEPCK as first reaction of gluconeogenesis
- PEPCK induced (increase synthesis by DNA transcription) by glucocorticoids (cortisol) during
starvation; PEPCK synthesis inhibited by insulin in fed state
3. Biotin
- a prosthetic group cofactor for enzymes catalyzing carboxylation reactions
- four reactions that require biotin are pyruvate carboxylase, MCC (leucine catabolism), PCC
(metabolism of met, ile, val and oxidation of fatty acids), acetyl-CoA carboxylase (ACC)
- biotin is covalently attached to a lysine residue on apoenzymes in a reaction catalyzed by
holocarboxylase synthetase
- when holoenzymes (apoenzymes + biotin) are degraded  biocytin (biotin + lysine
conjugate) released  biotinidase cleaves biocytin to recycle biotin
- human requirements for biotin met through synthesis by intestinal bacteria
- apparent biotin deficiency caused by genetic defects of carboxylases, holocarboxylase
synthetase or most commonly biotinidase
4. Fructose-1,6-BPase (FBPase-1)
- forms a futile cycle with PFK-1
- if PFK-1 and FBPase-1 were not reciprocally regulated, ATP would be hydrolyzed by PFK-1
with the phosphatase releasing phosphate rather than replacing the ATP  energy lost without
conservation
- disengaging this regulation occurs naturally and produces heat for the shivering reflex
5. Glucose-6-phosphatase
- produces glucose from glucose-6-phosphate (produced from gluconeogenic pathway)
- glucose-6-P transported into ER for dephosphorylation; glucose-6-Pase resides in ER
- glucose and Pi are returned to the cytoplasm
- glucose is exported to the blood and Pi remains in the cell
6. Reactions common to gluconeogenesis and glycolysis
- remaining enzymes in gluconeogenesis are reverse reaction of glycolysis; convert two
molecules of PEP  one molecule of fructose-1,6-BP
- one of the two molecules of glyceraldehyde-3-P intermediate must be converted to
dihydroxyacetone phosphate
- two molecules of ATP (phosphoglycerate kinase) and NADH (glyceraldehyde-3-P
dehydrogenase) are required to produce fructose-1,6-BP
Metabolism of key gluconeogenic precursors
- primary precursors for hepatic glucose production are lactate (40%) and alanine (25%), which
are first converted to pyruvate via LDH and alanine aminotransferase
- pyruvate carboxylated to oxaloacetate via pyruvate carboxylase
- for other amino acids to serve as precursors to glucose, they must be converted to pyruvate or
a citric acid cycle intermediate
- substance converted to acetyl CoA cannot be a precursor to glucose, because it is consumed in
the citric acid cycle and PDH is irreversible
Lactate as a precursor
- lactate is the primary source of carbons for gluconeogenesis
- it is derived from other RBCs or from muscle cells during exercise
- lactate  glucose pathway includes both pyruvate carboxylase and PEPCK in
mitochondrial matrix
- PEPCK product PEP transported to cytoplasm for gluconeogenesis completion
- need for NADH during reversal of glyceraldehyde-3-P dehydrogenase, but lactate provides
this directly in the cytoplasm via lactate dehydrogenase (LDH)
Alanine as a precursor
- most important amino acid serving as a precursor to glucose
- alanine as substrate  pyruvate produced via alanine aminotransferase
- produced in large amounts in muscle (short-term starvation up to one week)
7. Glycogen storage diseases
Type 1: Von Gierke disease; Glucose-6-Pase defect
- hypoglycemia due to defect in final step of gluconeogenesis; affects only liver/renal tubule
cells
- decreased mobilization of glycogen produces hepatomegaly
- decreased gluconeogenesis causes accumulation of lactate  lactic academia
Type V: McArdle disease; skeletal muscle glycogen phosphorylase defect
- liver enzyme normal
- weakness/cramping of skeletal muscle after exercise
- no rise in blood lactate during strenuous exercise
- muscle contains a high level of glycogen with normal structure
Type VI: Hers disease; liver glycogen phosphorylase defect
- marked hepatomegaly due to a high level of glycogen with normal structure
- glucagon administration  no increase in blood glucose