Term
| what is the role of gluconeogenesis |
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Definition
Net formation of glucose from pyruvate
essentially the reverse of glycolysis
provides glucose in absence of dietary glucose
primarily happens in liver |
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Term
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Definition
carbohydrates
TCA intermediates like alpha-ketoglutarate, succinly COA, OOA
every AA except leucine and lysine
triglycerides |
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Term
| enzymes specific for gluconeogenesis |
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Definition
glucose 6-phosphatase (reverse of step 1 in glycolysis)
fructose-1,6 bisphosphatase (reverse of step 3)
pyruvate carboxylase and PEP carboxykinase (reverse of step 10) |
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Term
| role of pyruvate carboxylase |
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Definition
It converts pyruvate to to OOA in the mitochondria
contains biotin, uses C02 from bicarbonate
activated by acetyl CoA
requires K+, Mg 2+, also ATP
ATP/ADP is high OOA used for gluconeogeneis
low, OOA is used in TCA |
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Term
| Role of PEP carboxykinase |
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Definition
After OOA exits the mitchondria through the malate-aspartate shutte, it converts it to PEP
It uses GTP, requires K+, Mn 2+
primarily but not exclusively cytoplasmic enzyme |
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Term
| Role of fructose 1,6-bis-phosphatase |
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Definition
Reverses action of PFK-1
converts fructose 1,6 BP to fructose 6 phopshate
allosterically inhibited by AMP and fructose 2,6 BP
rate limiting enzyme of gluconeogenesis |
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Term
| Role of glucose-6-phopshatase |
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Definition
converts glucose 6-phosphate to glucose
located in lumen of RER in liver and kidney medulla (membrane bound)
notably absent in CNS and RBC's |
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Term
| Role of lactate in supporting liver gluconeogenesis |
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Definition
Gluconeogenesis uses lactate in the Cori cycle
In RBC's along with other tissues pyruvate is converted to lactate by lactate dehydrogenase
Lactate is transported to the liver and converted to pyruvate which is then used in gluconeogenesis
there is a net consumption of energy
Cori cycle is important in regulating the amount of lactate in the blood |
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Term
| Role of alanine in supporting liver gluconeogenesis |
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Definition
Alanine can also be produced from pyruvate in peripheral tissues
Alanine can be transported to the liver
The “carbon skeleton” can be re-converted to pyruvate (and thus to glucose)
The nitrogen is processed via the “urea cycle” |
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Term
| Role of Acetyl CoA in gluconeogenesis |
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Definition
acetyl CoA (2C) must be condensed with oxaloacetate (4C) in order to enter the TCA cycle (citrate)
citrate (6C) is decarboxylated, ultimately yielding oxaloacetate (4C)
therefore there is no net flow of carbons from acetyl CoA to glucose(this includes Acetyl CoA from fatty acid b-oxidation)
however, acetyl CoA does act as an allosteric stimulator of pyruvate carboxylase, thereby stimulating gluconeogenesis |
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Term
| What is the reciprocal regulation of gluconeogenesis and glycolysis |
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Definition
Fructose 1,6 BPase is inhibited by AMP and F-2,6 BP
It is stimulated by citrate
PEP carboxykinase is inhibited by ADP
Pyruvate carboxylase is inhibited by ADP
Pyruvate carboxylase is stimulated by Acetyl CoA
Glucagon stimulates gluconeogenesis
inhibitors and stimulators switch roles b/t glycolysis and gluconeogenesis |
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Term
| What affect does ethanol metabolism have on gluconeogenesis? |
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Definition
Effects of ethanol metabolism on liver metabolism result primarily from accumulation of NADH within hepatocytes
decreased liver NAD+ inhibits both gluconeogenesis from lactate, and fatty acid oxidation (both require NAD+ and produce NADH).
reactions using NAD+ as cofactor are affected
result is increased ratio of lactate/pyruvate (shifted to lactic acidosis)
also decreased malate/oxaloacetate ratio (TCA cycle inhibited)
because fatty acid oxidation is inhibited, triglyceride accumulation in liver is increased (fatty liver) |
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Term
| Role of triglycerides in gluconeogenesis |
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Definition
Triglycerides can be metabolized to:
glycerol (glucogenic)
fatty acids (propionate from odd numbered f.a. is glucogenic)
Therefore, oxidation of lipids:can provide some precursors for gluconeogenesis, and provides energy (ATP) for gluconeogenesis |
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Term
| What is the role of fatty acid oxidation in gluconeogenesis? |
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Definition
During “fasting state” – (blood glucose drops)
liver can metabolize triglycerides, thus providing acetyl CoA and ATP
ATP, citrate and acetyl CoA are allosteric stimulators of gluconeogenesis |
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Term
| How is ethanol metabolized? |
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Definition
Ethanol is oxidized to acetate primarily in the liver
via a two-step pathway:
(1) Ethanol (CH3-CH2OH) + NAD+ = Acetaldehyde CH3-CHO) + NADH + H+
- catalyzed by alcohol dehydrogenase (ADH), cytosol of hepatocytes
(2) Acetaldehyde (CH3-CHO) + NAD+ = Acetate (CH3-COO-) + NADH + H+
catalyzed by aldehyde dehydrogenase in the mitochondrial matrix
acetate is converted to Acetyl-CoA (at the expense of ATP) by thiokinase (acyl CoA synthetase) |
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Term
| What is the structure of glycogen? |
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Definition
polymer of glucose with alpha 1,4 glycosidic linkages
a-1,4-glycoside (amylose) chain reaches 10-11 residues,
it becomes a substrate for the branching enzyme, which can remove a block of six or seven glucose residues and transfer them to a neighboring amylose chain, forming a a-1,6-glycosidic linkage.
Each new branch chain is introduced at least four residues from the nearest branch point. |
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Term
| Importance of glycogen storage in liver and muscle |
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Definition
Advantages of storing glucose as glycogen:
(a) the glucose polymer is osmotically stable
(b) glucose can be mobilized quickly when blood glucose is low
(c) glycogen can be used for energy generation even in the absence of oxygen |
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Term
| How is glycogen synthesized |
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Definition
Glycogen synthesis proceeds by ‘activation’ of glucose molecules which are then coupled to a growing glycogen polymer.
hexokinase
1) glucose > glucose-6-phosphate
phosphoglucomutase
2) glucose-6-P > glucose-1-phosphate
glucose-1-P uridyl transferase
3) glucose-1-P + UTP > UDP-glucose + PPi (pyrophosphate)
4) glucose residues are added by the enzyme glycogen synthase - these are added to the "primed" glycogenin molecule which already contains a glucose chain on it
5) the reducing end (C1) of UDP-glucose reacts with C4 of glucose on the end of the polymer, forming a a-1,4-glycosidic linkage,therefore, each glycogen molecule has only ONE reducing end ! (reducing end is at C1 of glucose) |
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Term
| How is glycogen synthesis initiated? |
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Definition
Glycogen synthesis begins with addition of the reducing end of a glucose molecule (from UDP-glucose) to the carrier protein glycogenin (37-kd) using a glucose transferase enzyme.
Thus, glycogenin is a glycoprotein – post-translationally modified in the endoplasmic reticulum.
Glycogenin itself (self-catalyzed, separate enzyme not required) then appears to catalyze the addition of three to eight additional glucose units to the growing polymer, generating a “primed” glycogenin molecule. |
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Term
| How is glycogen degraded to liberate glucose? |
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Definition
mobilization of glucose from glycogen stores by phosphorolysis
in muscle – glucose for immediate local use in ATP generation
in liver – functions to release glucose into the bloodstream
accomplished by the enzyme glycogen phosphorylase
cleaves the a-1,4-glycosidic bond (phosphorolysis) at the non-reducing end of polymer, yielding glucose-1-phosphate
glucose-1-P is converted to glucose-6-P by phosphoglucomutase and can then enter the glycolytic pathway
a debranching enzyme removes the last four residues of each branch, transferring three residues to the end of a glucose chain
the glucose residue at the branch point is released by hydrolysis |
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Term
| What is the role of cascade mechanisms in glycogen synthesis? |
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Definition
covalent modification (phosphorylation) is important
- phosphorylated form (synthase b) is less active and sensitive to stimulation by glucose-6-P
- dephospho form (synthase a) is fully active and is NOT sensitive to stimulation by glucose-6-P
cAMP, diacylyglycerol,and Ca2+ all stimulate the conversion of synthase a to synthase b as 2nd messengers
cAMP inhibits the reverse reaction of synthase b to synthase a |
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Term
| How is glycogenolysis regulated? |
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Definition
- glycogen phosphorylase is regulated by phosphorylase kinase
- phosphorylase kinase is activated by phosphorylation
by cyclic AMP-dependent protein kinase A
- glucagon and epinephrine, which raise the level of cyclic AMP,promote glycogenolysis
- insulin stimulates protein phosphatase, lowers cAMP level, inhibits glycogen phosphorylase |
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Term
| What is Von Gierke Disease |
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Definition
Type 1 glycogen storage disease
defective enzyme is glucose 6-phosphatase or transport system
increased amount of glycogen, normal structure
massive liver enlargement, |
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Term
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Definition
Type II glyocgen storage disease
defective enzyme is alpha - 1,4 glucosidase (lysosomal)
massive increase in glycogen, normal structure
cardiorespiratory failure, usually die before age 2 |
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Term
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Definition
Type V glycogen storage disease
defective enzyme is phosphorylase
moderately increased amount in glycogen
painful muscle cramps limits ability to perform strenous exercise |
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Term
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Definition
defined as accumulation of lactate, usually in response to decreased availability of oxygen.
interruptions in the TCA or ETS can lead to accumulation of lactate
failure of gluconeogenesis (due to enzyme deficiency or something else) can result in lactic acidosis
- pyruvate will not converted to glucose so more of it will be converted to lactate especially when oxygen availability is low |
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