Metabolism Flashcards
How do GLUT and hexokinase features fit with the function of the tissue in which they are expressed?
GLUT 1 / 3 and HK 1 in Brain and many tissues. Low Km, high affinity for glucose to maximize response.
GLUT 2 / HK 4 (glucokinase) in liver and pancreas. High Km, low affinity for glucose to allow for regulation of response to increased glucose levels.
GLUT 4 / HK 2 in adipose and skeletal muscle. Low Km, high affinity. Insulin dependent. GLUT 4 transported to surface when insulin stimulated, esp in response to high blood sugar. Glucose taken in from bloodstream, and blood glucose decreases.
What are the structural features of ATP that contributes to functionality in metabolism?
High energy bonds
Electron repulsion - negative charges on phosphates destabilizing
Resonance - phosphate or pyrophosphate have more resonance opportunities when free than as ATP
What are the structural features of glycogen that contributes to functionality in metabolism?
Branched (Alpha 1-4 chains, Alpha 1-6 branches)
One reducing end, several non-reducing
1. Significantly lower osmotic impact than glucose
2. More soluble than linear polymers (lack of branching enzyme = liver cirrhosis)
3. Multiple non-reducing ends to initiate efficient and rapid glycogen degradation
What are the irreversible steps of glycolysis, and how are they circumvented for gluconeogenesis?
1.) Glucose + ATP -> G6P via hexokinase
G6P -> Glucose via G6Pase in LIVER and kidney only (sequestered in ER)
2.) F6P + ATP -> F16P via phosphofructokinase (PFK)
F16P -> F6P via fructose 1,6-bisphosphatase
*F26P is potent activator of PFK. Under fasting state, PKA phosphorylates kinase domain of bifunctional enzyme, to inactivate production of F26P. Phosphatase activity continues to degrade F26P. With less F26P, glycolysis is not activated. Gluconeogeneis is favored (LIVER and kidney). (Muscle bifunctional enzyme lacks Ser residue in kinase domain and cannot be phosphorylated. Glycolysis essentially always active in muscle.)
3.) PEP -> pyruvate + ATP via pyruvate kinase (PK)
Pyruvate -> oxaloacetate via pyruvate carboxylase (PC) (oxaloacetate -> malate via malate dehydrogenase – mit to cyt – malate -> oxaloacetate via malate DH) oxaloacetate -> PEP via PEP carboxylase
What phenotype is expected in deficiency of glucose-6-phosphatase?
Type I GSD (Von Gierke's) Liver and Kidney affected Massive enlargement of the liver Failure to thrive Severe hypoglycemia Ketosis Hyperuricemia Hyperlipemia
What phenotype is expected in deficiency of glucokinase?
Affects pancreas No insulin produced Hyperglycemia Essentially diabetes High glucagon Weight loss Low insulin Hyperglycemia Hyperlipemia?
What phenotype is expected in deficiency of ATP-senstive K+ channel?
If deficient so channel can't open: Constant membrane depolarization Ca2+ channel opening and influx High activity of Ca2+ dependent kinases High insulin secretion Phenotype - increased insulin Hypoglycemia
If deficient so high ATP can't inhibit (constitutively open): No membrane depolarization No Ca2+ channel opening/infulx No Ca2+ dependent kinase activity No insulin secretion Phenotype - essentially diabetes Hyperglycemia Weight loss
What phenotype is expected in deficiency of branching enzyme?
Type IV GSD (Andersen's) Liver and spleen affected Long branches Progressive cirrhosis of liver Liver failure
What phenotype is expected in deficiency of debranching enzyme?
Type III GSD (Cori’s)
Muscle and liver affected
Like Type 1, but milder
(hypoglycemia, ketosis, hyperuricemia, hyperlipemia)
What phenotype is expected in deficiency of muscle glycogen phosphorylase?
Type V (McArdle’s)
Limited ability to perform strenuous exercise, painful muscle cramps
Otherwise normal
What phenotype is expected in deficiency of ornithine transcarbamoylase?
Hyperammonia, accumulation of glycine and glutamate
Lethargy, come, brain damage
(Treat with protein-restricted diet, large amounts of benzoate or phenylacetate)
What distinguishes GLUT from SGLT type glucose transporters?
GLUT uniporters - passive - relies on phosphorylation to G6P to maintain glucose gradient (glucose goes in)
SGLT secondary active symport - uses Na+ gradient established by Na+K+ ATPase to bring Na+ inside cell along its gradient and pull glucose inside cell against its gradient
How does islet cell architecture and blood flow relate to reciprocal control of insulin and glucagon secretion?
Arterial blood reaches center first, which is where the beta cells (insulin producing are). Blood gets insulin first. Level of insulin determines how much glucagon (from alpha cells on periphery) is introduced. High insulin inhibits glucagon secretion.
How is insulin secretion regulated in the postprandial (fed) state?
Fed state, high glucose levels GLUT 2, HK 4 (glucokinase) Glucose to G6P - catabolism Increase in ATP:ADP ratio Inhibits ATP sensitive K+ channel
What are key components of the pyruvate dehydrogenase enzyme complex and what are the functions of the individual components and cofactors?
E1: TPP (thiamin) - oxidative decarboxylation of pyruvate (TPP forms covalent intermediate with pyruvate)
E2: lipoamide (long arm to swing between components) - transfer of acetyl group to CoA
E3: FAD (riboflavin) - regeneration of the oxidized form of lipoamide
PDH in mitochondria
Inhibited by byproducts of fatty acid oxidation (acetyl-CoA, ATP, NADH) - allosterically act on E1 as well activate kinases on E2 that phosphorylate E1 and inhibit
pyruvate (kept acid) + CoA (adenine ring, ribose) + NAD -> Acetyl-CoA (acyl-CoA) + CO2 (decarboxylation) + NADH
Similar mechanism / reaction for alpha-ketoglutarate DH and BCKDH (branch chain kept-acid DH)
