Sugar-advanced metabolism Flashcards
a sum of enzyme-catalyzed reactions by which a living cell perpetuates and
replicates itself
Metabolism
Intermediary/Energy metabolism:
A SET OF REACTION concerned with..
- generation or storing energy and with
- using that energy for biosynthesis of small molecules.
Metabolism is associated with maintenance of cellular ______ & blood _______ levels
ATP, glucose
using energy
derived from
catabolic
pathways;
endergonic
process
Anabolic process biosynthesis pathway
Oxidative breakdown
of complex larger
molecules that
results in energy
release captured by
formation of high
energy compounds
(ATP); exergonic
process
catabolic
a metabolic pathway that can be both, catabolic and anabolic
Amphibolic
sugars with names containing the suffix -ose.
Saccharides
Monosaccharides are stereoisomers:
* All monosaccharides in humans are…
D-stereoisomers
Most stable confirmation of saccharides are ring structures.
What are the ring structures?
Six member rings (pyranose) & five membered ring (furanose)
OH- group at position 1 in saccharides can adapt in ____or ____ confirmation.
which is more stable?
α or β
The β confirmation is more stable in glucose but polysaccharides (starch) and glycogen have glucose linked in the α confirmation.***
Which complex carbohydrates is nutritionally most important?
Disaccharides
-maltose(glucose+glucose)
-lactose(glucose+ galactose)
-sucrose( glucose+ fructose)
Complex carbohydrate that contain 2 to 10 monosaccharide units
Oligosaccharides
Complex carbohydrate that is greater than 10 monosaccharide units
Polysaccharides
-Cellulose
* Starch
* Glycogen
* Glucan: Polysaccharide of D-glucose monomers
What are the other (minor) carbohydrates?
glycogen, alcohol, lactic acid, pectin & dextran
Polysaccharide starch: source of ___% of monosaccharides
80
When does amylase action begin? end?
Starts in the mouth, continues in stomach to hydrolyze starch into maltose and other small polymers of glucose.
ends in about an hour, gastric secretions inhibit activity.
after chyme enters duodenum, pancreatic amylase is added.
Disaccharides & oligosaccharides need to be converted to ___________ before absorption.
monosaccharides
Chyme enters jejunum and ileum where four enzymes are located in the brush border of cells
lining the intestine, which are… ?
lactase, sucrase, maltase, & α-dextrinase.
–Monosaccharides are immediately absorbed into the portal blood.
What are the Glucose transporters used to get glucose across cell membranes?
GLUT-1, GLUT-2, GLUT-3, GLUT 4 & GLUT-5
Glucose transporter that…
has low affinity (high Km) to glucose.
* Found in areas with high glucose concentrations.
* Involved in insulin-independent glucose in small intestines, renal tubules &
liver
GLUT-2
Glucose transporter that…
has a high affinity (low Km) to glucose.
* Found in glucose-sensitive, insulin independent cells of the brain & RBC.
GLUT-1, GLUT-3 & GLUT-5
Glucose transporter that…
has an intermediate affinity to glucose
* Found in insulin-dependent muscle & adipose cells.
GLUT-4
storage form of glucose in muscle &liver
Glycogen (Polymeric glucose)
major source of energy & primary form of nutrition
Monosaccharide
Monosaccharides can be transformed into what metabolites?
- Glucose to ribose
– Glucose to oxidized / reduced forms, such as mannitol, glucuronic acid
–> important constituents of complex polysaccharides
Other functions of carbohydrates?
» Long chains of hyaluronic acid and keratin sulfate makeup components of synovial
fluid and connective tissue
» Heparin
» Integral proteins
» Secreted proteins
Fructose is Primarily metabolized in…
liver, kidney, and small intestine
In the liver, fructose is converted to?
In other tissues?
-fructose-1-p by fructokinase
-Phosphorylated by hexokinase
What are three disorders of fructose metabolism?
-Essential fructosuria
-Hereditary fructose intolerance
-Hereditary fructose-1,6-bisphosphatase deficiency
this disorder of fructose metabolism won’t effect glycolysis
Hereditary fructose-1,6-bisphosphatase deficiency
What is known as false diabetes mellitus?
Essential fructosuria
Disorder of fructose metabolism:
results from a deficiency of
fructokinase in the liver
Essential fructosuria
Disorder of fructose metabolism:
results from a
deficiency of fructose-1-p aldolase of liver, kidney cortex and small intestine
Hereditary fructose intolerance
What are the disorders of Galactose metabolism?
-Classic galactosemia
-Galactosemia due to loss of galactokinase (GALK)
-Epimerase deficiency (GALE)
Disorders of Galactose metabolism:
due to loss of uridylyltransferase
(GALT)
Classic galactosemia
Disorders of Galactose metabolism:
Galactosemia due to loss of galactokinase (GALK)
- Both are lactose intolerant, can lead to blindness and fatal liver damage
Galactosemia due to loss of galactokinase (GALK)
Disorders of Galactose metabolism:
– 2 forms,
1) benign, 1) similar to transferase deficiency
Epimerase deficiency (GALE)
the liver controls blood glucose concentrations, how?
-Via glycogen levels
* Converts intestinally absorbed galactose & fructose to glucose
* Produces glucose via gluconeogenesis (glucose-6-phosphatase activity)
Liver also responsible for producing important glucose metabolites, like?
-Ribose
-Oxidizes/reduces to form complex monosaccharides
What is the primary energy source used by the brain?
Sugar
Glucose can make up to ___ pyruvate and _____ Acetyl CoA.
2, 2
Building up to glucose is called?
And breaking down glucose is called?
gluconeogenesis (Using non-carb sources to make glucose)
glycolysis
which is limited? which is unlimited storage?
glycogen storage is limited!
-not all Acetyl CoA can be processed to the TCA cycle
fat storage is unlimited
what is the storage form of glucose?
Glycogen
How is ATP and ADP related?
ATP/AMP:ADP:P* ratio
What influences the metabolic rate?
ATP levels
What is a major difference in HDL and LDL?
HDL-moves cholesterol to liver to be cleared
LDL-moves cholesterol to peripheral circulation
What is the starting point of the TCA cycle?
What is it also important for?
oxaloacetate
gluconeogenesis
Where is NAD+ and NADH mainly found?
NAD+- mitochondria
NADH- cytosol
What is the difference between alpha and beta confirmations?
?
If carbon #1 and carbon #5 is linked by oxygen —> alpha confirmation.
How can you distinguish D-glucose from L-glucose?
-Look at the second to last carbon
-OH group on the right side —> D-glucose
-OH group on the left side —> L-glucose
What is maltose made up of?
2 glucose
What is lactose made up of?
glucose and galactose
What is sucrose made up of?
glucose and fructose
Only ___________ form of sugar can enter the cells.
monosaccharide
a minor carbohydrate that can be used as a blood thinner. It is very large and can also be used for patients with low blood volume.
dextran
If the first carbon has the OH group on top it is alpha or beta confirmation?
Beta
Km =
1/2 Vmax
What are the two processes involving glycogen?
-Glycogenesis
-Glycogenolysis
What are the two processes involving glucose?
-Glycolysis
-Gluconeogenesis
*Hexose MonoPhosphate Shunt
___________ produces the storage form of glucose: high MW polysaccharide composed of glucose.
Glycogenesis
Glycogenesis:
linked with a _______ glycosidic bonds and branches with ________ glycosidic bonds (every 10 untis*)
α (1–>4)
α (1–>6)
Where does glycogenesis occur?
cytoplasm (liver and muscle)
What is step #1 of glycogenesis?
glucose-6-phosphate is catalyzed by phosphoglucomutase to glucose-1-phosphate
What is step #2 of glycogenesis?
glucose is activated with UTP which is catalyzed by UDP-glucose pyrophosporylase to UDP-glucose
What is step #3 of glycogenesis?
glycogen synthase adds UDP-glucose to growing glycogen molecule.
What can glycogen synthase (GS) be controlled by?
by phosphorylation or dephosphorylation
Glycogen synthase (GS) is regulated by?
cAMP-dependent PKA phosphorylation
-GS activity inhibited by PKA phosphorylation***
- Hormones that increase cAMP (___________& __________) activate PKA. [inhibit glycogen formation]
glucagon, epinephrine
**GS activity is ___________ if phosphate is removed.
increased
Branching enzyme attaches ___ to __glucose units to glycogen via α (1–>6) glycosidic bonds
5, 6
________________ phosphatase removes phosphate group & as cAMP concentrations decline, glycogen
formation is increased
Insulin-regulated
What is the major point of regulation for glycogen synthesis?
Branching enzyme***
The process involved in producing glucose from glycogen?
Glycogenolysis
Glycogenolysis:
What cleaves glycogen to glucose-1-phosphate
Glycogen phosphorylase
Glycogenolysis:
Glycogen phosphorylase activity is increased following phosphorylation by ___________ which activated by ______.
phosphorylase kinase
PKA
Glycogenolysis:
*What does hormones that increased cAMP (glucagon and epi) do to PKA?
activates PKA so that glucose-1-phosphate formation increases
Glycogenolysis:
______________ converts glucose-1-phosphate into glucose-6-
phosphate
Phosphoglucomutase
Glycogenolysis:
__________________ removes phosphate in glucose is free to diffuse from liver into the circulation
(liver) glucose-6-phosphatase
-This is an old metabolic pathway, fully functional under Anaerobic conditions
-Essential for cells unable to function aerobically (have no mitochondria)
Glycolysis
What cells rely on glycolysis?
**RBC & some cells in the eye (lenz and retina)
What cells/organism undergo glycolysis?
all types
Where does glycolysis take place?
Hoe much energy does it extract from glucose?
cytosol
less than 5%
What are the three enzymes needed for glycolysis? **
(Steps 1,3, and 10) step 6 is the connecting point?
-Hexokinase
-phosphofructo-kinase-1
-pyruvate kinase
Is glycolysis reaction #1-phosphorylation reversible or irreversible?
irreversible
liver or brain?
Hexokinase-
glucokinase-
Hexokinase-body
glucokinase-liver?
Glycolysis Reaction #1:
Catalyzed by Glucokinase in the _____ or Hexokinase in ______.
liver, muscle/fat
Glycolysis Reaction #1:
– Traps glucose inside the cell – charge at physiological pH
– Conserves metabolic energy
– Phosphates interact with enzyme active sites and lower activation energy
-Mg used as a cofactor
cf. Phosphorylation:
Glucokinase (Liver) is highly specific for ________.
Glucose
Glucokinase has a ___ Km for glucoase (about ___mM)
high, 10
-Not saturated at physiological blood glucose concentration
(4-5mM)
Glucokinase is inhibited by __________, but NOT __________.
fructose-6-phosphate
glucose-6-phosphate
Glucokinase is induced by __________.
insulin
What is the specificity of hexokinase?
Low specificity – phosphates most relevant hexoses
(Glucose, Fructose, Mannonse)
hexokinase has a _____ Km (___mM): saturated at all plasma glucose
concentrations
low, 0.1 (increased affinity)
-x100 lower than glucokinase
Hexokinase is inhibited by..,
glucose-6-phosphate (fructose and others?)
What effect does insulin have on hexokinase?
little effect on expression
*** In RBCs, rates of glycolysis is regulated by _________.
ATP/AMP+ADP
-Increased ATP or not enough ADP, glycolysis will shutdown*
Regulation of Glycolysis:
- 3.
- Hexokinase/Glucokinase
- Phophofructokinase-1 (PFK-1)
- Pyruvate Kinase
Regulation of Glycolysis, Phophofructokinase-1 (PFK-1):
activated by:
inhibited by:
activated by: AMP, F-2, 6-BP
inhibited by: ATP, citrate
Regulation of Glycolysis, Pyruvate Kinase:
activated by:
inhibited by:
activated by: F-1, 6BP
inhibited by: ATP, Acetyl CoA, Alanine
Glycolysis reaction #6:
- Anaerobic conditions:
- Aerobic conditions:
- Anaerobic conditions: conversion of pyruvate to
lactate by lactate dehydrogenase - Aerobic conditions: by Shuttles which passes H+ to
the mitochondrion.
What are the two major shuttles under aerobic conditions?
-Glycerol phosphate shuttle
-Malate-Aspartate shuttle
What is the reverse pathway of glycolysis?
Gluconeogenesis
gluconeogenesis is a process that produces glucose-6-phosphate from what three things?
-AA
-FA
-glycerol and lactate
Gluconeogenesis:
Glucose is only formed in ______ and ______: Glucose-6-phosphatase
*** liver, kidney
What are the primary pursers for glucose synthesis?
– Glucose only formed in liver & kidney: Glucose-6-phosphatase
– Lactate goes pyruvate,
– Alanine goes to pyruvate,
– Glycerol goes to glyceraldehyde-3-phosphate
*** Hexose Monophosphate Shunt
Pentose Phosphate Pathway:
produces ______ in two-step pathway.
-Oxidative & non-oxidative steps
ribose
Why is ribose and NADPH needed from the pentose phosphate pathway?
*Ribose used to produce nucleotides and nucleic acid
*Pathway produces NADPH which is important reducing agent for biosynthetic process ex) FA & Cholesterol synthesis
“Alternative glucose oxidation pathway”
Hexose Monophosphate Shunt
Pentose Phosphate Pathway
Hexose Monophosphate Shunt
Pentose Phosphate Pathway:
Which tiesues?
- Active in FA & steroid synthesis: adrenal gland, liver, adipose tissue &
mammary gland - RBCs: Maintain their membrane integrity.
- Rapidly dividing cells: require DNA synthesis
(Length of survival depends on this pathway)
Pentose phosphate pathway can be divided into what two parts?
1) Oxidative and 2) non-oxidative “A kind of “recycle pathway”
What are the organs and glands involved in hormonal regulation of carbohydrates?
-Pancreas
* Insulin (hypoglycemic)
* glucagon
* somatostatin
– Adrenal gland
* Cortisol
* epinephrine
– Thyroid
* thyroxine
– Pituitary (anterior)
* Growth hormones
Insulin-dependent diabetes is which type ____
1
Where is insulin synthesized from?
islet of Langerhans β cells of pancreas as preproinsulin.
-packaged in beta granules
Insulin:
➢ Enzymatic cleavage of pre-proinsulin first forms proinsulin
✓ goes to….
insulin + C-peptide
INSULIN consists of an α & β chain connected by _____ bonds
s-s
Insulin released from β cells after what stimulations?
neural, dietary or hormonal stimulation (GIP, Somatostatin, Bombesin)
Glucose, amino acids increase _____________ peptide which increase insulin.
gastric inhibitory
What are the major target organs of insulin action?
- Liver which decreases proteolysis, lipolysis, gluconeogenesis, and
glycogenolysis - Muscle which increase protein synthesis
- Fat which increases triglyceride synthesis
Glucagon is Synthesized in islet of Langerhans ___ cells of the pancreas
alpha
what increases glucagon release?
AA & exercise
Secretion of glucagon is potent & irreversibly regulated by…
[glucose]blood
Increased glucagon increases what?
-increased glycogenolysis: activates PKA & phosphorylase kinase
–increased gluconeogenesis,
– ketogenesis by inhibiting
storage of TG in liver
– Fat increases lipolysis
Synthesized in islets of Langerhans δ cells of pancreas
Somatostatin (GI paracrine)
what is the circulatory half-life of somatostatin (GI paracrine)?
short, about 2 min
What is somatostatin released with?
[glucose]blood, AA, FA & GI hormones
Somatostatin acts locally to __________ insulin and glucagon secretion.
decrease
-The effect is to increase for period of time which did nutrients are
assimilated into the bloodstream
Cortisol:
glucocorticoid is released from the adrenal ________.
The secretion is regulated by ______.
cortex
ACTH
Cortisol results in increased blood glucose due to….
-increased gluconeogenesis in the liver
–increased enzymes in GLUCONEOGENESIS pathway
– Mobilization of AA from extra hepatic tissue
Epinephrine released from ___________ after stimulation
of SYMPATHETIC NERVES
adrenal medulla
How does epinephrine result in increased blood glucose?
-decreased insulin secretion
-increased glucagon secretion
-increased glycogenolysis
-increased
gluconeogenesis
Thyroxine (T4) results in an overall ________ in protein synthesis. What else does it increase?
protein
-in glucose uptake
-in glycolysis
-gluconeogenesis
-rate of glucose absorption from intestinal tract
-Also results in increased
insulin but a secondary to
increasing
blood glucose
What is an important effect of thyroxine (T4)?
increased rate of glucose absorption from intestinal tract***
*** GH counteracts “in general” the effects of…
insulin on glucose & lipid
metabolism, but shares protein anabolic properties with insulin.
GH results in an overall increase in blood glucose as a result of….
-decreased utilization glucose for energy
- increased in glycogen deposition in cells
-decreased uptake of glucose by cells —> increase blood glucose
What is the enzyme used for oxidative decarboxylation?
Pyruvate dehydrogenase complex
Lipoate, TPP, FAD
Is oxidative decarboxylation reversable?
no
Oxidative Decarboxylation:
Involves both, oxidation-reduction and decarboxylation.
What agent always participates?
✴ NAD+ & NADP+ or other oxidizing agent always participates.
Is Oxidative Decarboxylation endergonic or exergonic?
always exergonic ΔG< 0
_____________________ always participates in oxidative decarboxylation &
often in simple decarboxylations
Thiamine pyrophosphate
Oxidative Decarboxylation:
The overall reaction is ____________ : FA cannot be converted into carbohydrate
irreversible
What is the allosteric regulation of PDH?
– Inhibition by ATP, acetyl-CoA and NADH
– Activation by AMP, CoA and NAD+
What is the covalent regulation of PDH?
– Activation by dephosphorylation [PD phosphatase]
– Inhibition by phosphorylation of E1(pyruvate dehydrogenase)
(by PD Kinase activated by ATP)
REFREASH TCA CYCLE
!
What is the prime site of the TCA cycle?
oxaloacetate
What are the three enzymes that regulate the TCA cycle?
-Citrate synthase
-Isocitrate dehydrogenase
-α-Ketoglutarate dehydrogenase
Key sites of Regulation of TCA:
Citrate synthase is inhibited by…
ATP, citrate, NADH and succinyl-CoA
Key sites of Regulation of TCA:
Isocitrate Dehydrogenase is inhibited by…
ATP, alpha ketoglutarate, and NADH
Key sites of Regulation of TCA:
α– Ketoglutarate dehydrogenase is inhibited by…
ATP, GTP, succinyl-CoA and NADH
Can pyruvate ONLY get into the TCA cycle through
decarboxylation?
No. Anaplerotic pathways.
-pyruvate carboxylase —> oxaloacetate (ATP-dependent carboxylation reaction)
-Malic enzyme —–> Malate (pro- and eukaryotes)
-oxaloacetate —> PEP by PEP-CK, heart and skeletal muscle (phosphoenolpyruvate carboxykinase)
Oxaloacetate is very important for…
gluconeogenesis
Where does gluconeogenesis mainly take place?
liver, not muscle
Gluconeogenesis:
7 out of 10 reactions are the reverse of __________.
glycolysis
The highly exergonic nature of the glycolysis is due to what reactions?
HK/GK, PFK-1, and pyruvate kinase reactions.
Three reaction cannot be reversible
Gluconeogenesis must get around the three irreversible reactions by a new set of exergonic reactions that drive the process in the _________ direction.***
opposite
What are the gluconeogenesis substrates?
-Lactate (pyruvate) – Cori cycle
-Glucogenic AA (all, except leu & Lys)
-Glycerol (from the breakdown of TG)
-All TCA intermediates
Is acetyl-CoA a TCA intermediate?
NO
What AA do NOT give you intermediates that fit into the TCA cycle?
leu and Lys
How is lactate (pyruvate) continuously produced?
-RBC metabolism
-excising muscles
Where are the majority of the enzymes responsible for gluconeogenesis are found?
cytosol, although some precursors are generated in the mitochondria
Cori cycle summary
[ Liver ] 2 lactate ->2 pyruvate –>(6) glucose
————>
[ Muscle ] glucose (2ATP) –> 2 pyruvate –> 2 lactate
back to liver (by blood)
Net consumption of 4 ATPs
The Cori cycle is very energy ___________.
inefficient
How is pyruvate converted to PEP?
first reaction…
A biotin-dependent carboxylation of pyruvate by pyruvate
carboxylase to yield oxaloacetate
primes the TCA cycle
How is pyruvate converted to PEP?
second reaction…
A decarboxylation by phosphorenolpyruvate carboxykinase
(PEPCK) to produce PEP
Conversion of OAA to PEP can occur through the action of cytosolic or mitochondrial PEP-CK
What is it for Ala?
What is it for Lac?
Alanine- cytosolic
Lactose-mitochondrial
Gluconeogenesis, which occurs in the cytosol, requires _______
NADH
NADH “must” be generated in the cytosol or imported from the mitochondria
How is NAD+ supplied for glycolysis?
What is important for regulating gluconeogenesis pathway?
-PEPCK
-fructose 1,6 bisphosphatase
???
PEP is converted to ______ by the glycolytic enzymes acting in reverse.
F-1,6-BP
The PFK-1 reaction is bypassed in by a simple hydrolytic reaction
catalyzed by ______________________.
Fructose 1,6 Bisphosphatase
***This step represents the “major site of regulation” of gluconeogenesis
The irreversible GK reaction is reversed by the action of ________________ (a simple hydrolysis).
➢ G-6-phosphatase is present in the liver & kidney.
- Glucose can thus leave the liver and enter the blood.
Glucose-6-phophatase
Gluconeogenesis:
***Carbon atoms for the synthesis of glucose are provided from ________ or _________.
This is why protein wasting is a prominent phenomenon during starvation
or Type 1 diabetes
What provides the necessary energy required by gluconeogenesis?
lactate, amino acids
*Lipid oxidation
What is the major regulation site of gluconeogenesis?
The major allosteric modulator of the activities?
PFK-1/Fructose-1,6 Bisphophatase couple
Fructose-2,6 bisphosphate
Phosphorylated PFK-2 (inhibited)- decreased levels of F-2,6 BP =
Inactivating PFK-1 & activating Fructose-1,6 Bisphosphatase
disease associated with increased production and metabolism of glucose
What are the types?
- Type I
– Type II
– Secondary
– Gestational
Type 1 diabetes accounts for ____% of all cases of diabetes and is usually diagnosed before the age of ____.
5-10, 20
Causes of type 1 diabetes?
inherited, autoimmune or infection
What are the complications of type 1 diabetes?
Retinopathy, Neuropathy, Nephropathy,
Angiopathy*
Hyperlipidemia, Ketoacidosis, increased susceptibility to infection & lactic acidosis
Clinical presentation of ketoacidosis patients?
low HCO3-, normal pCO2, high anion gap and [glucose]blood —> Low pH
What is the difference in type 1 diabetic and starvation induced ketoacidosis?
presence of hyperglycemia in type I diabetics and hypoglycemia in starvation.
____________ causes type I diabetes to use FA as an alternative
Insulinopenia
FA mobilized —-> increases acetyl-CoA
Excess AcCoA!acetoacetyl CoA –> HMG CoA
Type II diabetes accounts for _______ % of all diagnosed cases of diabetics
90-95
2% of Americans
often obesity related but appears to have a hereditary component
Onset of type II diabetes is usually after ____ years of age.
40
Type II diabetes is characterized by hyperglycemia and “presence of _________”
insulin
Diabetic ketoacidosis primarily occurs in type….
I diabetics; however,
can occur in type II diabetics
Gestational diabetes occurs in ____ % of pregnancies.
What causes it?
2-5
inability to secrete insulin towards the 4x increase in demand
What is the risk of gestational diabetes?
How is it treated?
-Hyperglycemia increases the risk of spontaneous abortion & birth defects
-Treated with insulin or hypoglycemia agents
What is the primary structural change in a protein happening with high blood glucose?
Covalent bonding of carbohydrates to proteins produced in presence of excess carbohydrates
elevation of GHb
The elevation of GHb occurs about ___ wks after sustained
elevation in blood glucose, and last ____ months
3, 2-3
What is used to assess adherence to insulin treatment?
Percent of glycosylated Hb (HbA1c)
What conditions/diseases is testing of HbA1c not good for? why?
-cystic fibrosis
-gest. diabetes
-pt. with chronic liver or kidney disease
-sickle cell anemia
because RBC turnover is too fast
Normal HbA1c %?
below 5.7%*
Prediabetes HbA1c %?
5.7-6.4%*
Diabetes HbA1c %?
6.5% or above*
HbA1c:***
* Child:
* Good diabetic control:
* Fair diabetic control:
* Poor diabetic control:
- Child:1.8-4%
- Good diabetic control: 7%
- Fair diabetic control: 10%
- Poor diabetic control:
13-20%
What is normal Glucose level range?
70-110 mg/dL
Decreased blood glucose concentration can result in mild to severe coma, seizures and death.
* Occurs when blood glucose is less than ____ mg/dL
50
Cf. According to ADA, less than 70 mg/dl
What are causes of hypoglycemia?
- Excess insulin
– Liver disease
– Alcoholism
– Renal insufficiency
– Malignancy (beta cell tumor)
– Infection
– Pregnancy
– malnutrition
Treatment for hypoglycemia
IV glucose
NADH Ethanol Metabolism…
-alcohol dehydrogenase converts, in the cytosol, EtOH to acetaldehyde & produces
NADH
* Acetaldehyde enters mitochondria and is oxidized by acetaldehyde
DH to acetate and generates NADH
The capacity to metabolize EtOH is dependent upon the ability to shuttle ______ into mitochondria.
NADH
In NADH ethanol metabolism, increased NADH inhibits….
gluconeogenesis, FA oxidation, &
glycerophosphate DH***
Hepatic Ethanol Toxicity:
NADH increases pyruvate to lactate, thus inhibiting pyruvate conversion to
glucose
(Inhibiting gluconeogenesis)
How does hepatic ethanol toxicity lead to “fatty liver” and hyperlipidemia?
-Acetate converted to acetyl-CoA, can’t be oxidized in TCA so converted to fat
-Inhibited glycerophosphate DH leads to more glycerophophate which
is a backbone of TGs,
Hepatic Ethanol Toxicity:
_______________ forms adducts with proteins, nucleic acids, leading to acute toxic effects
* EtOH inserted into membranes altering action potentials and depressing CNS function.
Acetaldehyde
Heparin is a type of
Is a mix of sulfonated polysaccharides
Glucuronic acid
helps remove harmful substances from the body
Is ethier a oxidized or reduced form of glucose
Galactose to
—-galactose kinase–> galactose 1 phosphate
- type two galactosemia
Galactose 1 phosphate
—uridylyltransferase with UDP-gal-glu-1-P—> glucose 1 phosphate
type one galactosemia
Glucose 1 phosphate to
—phosphoglucomutase–> glucose 6 phosphate
Glucose 6 phosphate–>
G-6-P—>F-6-P—>F-1,6-BP
Lactose goes to what and then what
Galactose then glucose 1 phosphate
Maltose goes to what and then what
Glucose and then glucose 6 phosphate
Mannose goes to what and then what
Mannose 6 phosphate and then fructose 6 phosphate
Sucrose goes to either what or what or what
Fructose—> fructose 6 P
Glucose—> Glucose 6 P
Fructose—> fructose 1 P—> Dihydroxyacetone or glyceraldehyde
Glycerol goes to what
A glycerol phosphate then Dihydroxyacetone-P
Fructose to F-6-P by
Hexokinase in other tissues
Glucose to
Glucose—> G-6-P—-> F-6-P—-> F-1,6 BF
Fructose in liver by Fructose kinase pathway
1.) Fructose—> Fructose 1 phosphate by Fructose Kinase and ATP is converted into ADP
2.) Fructose 1 Phosphate——> either Glyceraldehyde or DHAP by enzyme Fructose 1-P aldolase
3A.) Glyceraldehyde—-> Glyceraldehyde 3 phosphate by enzyme Triose kinase and ATP to ADP
3B.) DHAP—> Glyceraldehyde 3 phosphate with enzyme TIM
Glucose to G-6-P to
F-6-P—> F,1,6 BP
Glucose 1 phosphate—> UTP to PPi and enzyme UDP-glc pyrophosphorylase to UDP- glucose
1.) UTP to PPi and enzyme UDP-glc pyrophosphorylase to UDP- glucose
2.)
Ribose is a
Glucose metabolite
Glycogenesis
The formation of glycogen from sugar
Gluconeogenesis
The making of sugar from non carb sources
Glycogeneisis
Produces the storage form of glucose
High MW polysaccharide composed of glucose
Glycogen is linked
Linked with a (1–>4) glycosidic bond and branches with a (1—>6) glycosidic bond (every 10 units)
Mutase
Catalyses the movement of a functional group from one location to another
Kinase
Transfers of a phosphate group from a ATP molecular to another another molecule
Transferase
Catalyzes the transfer of a group from one molecule to another
Pyrophosphorylase
Catatalyses the nterconversion of glucocose 1 phosphate and Uridine triphosphate (UTP) to inorganic phosphate and UDP glucose
Glycogenin
Involves in the Convertion glucose to glycogen
Pyruvate to blank in aerobic conditions
Acetyl COA
Pyruvate to blank in anaerobic conditions
Lactate in RBC’s
NAD+ and FAD+ are special what
Proton acceptors
Oxidative form
NAD+ and FAD+
Reduced form
NADH and FADH
what is added to make NAD+ into NADH
a hydride ion H* + and a -
what are kinases
Recall that kinases are enzymes that catalyze the transfer of the terminal phosphoryl group from ATP to an acceptor nucleophile.
Step one glycolysis
one phosphate group are attached to one molecule of glucose 6 phosphate, ATP is converted to ADP with the help of Mg2+ and G10=-16.7 kj/mol
Hexokinases and magnesium
- The acceptor in the case of hexokinase is a hexose, normally D-glucose
- hexokinase also catalyzes the phosphorylation of other common hexoses, such as D-fructose and D-mannose.
- Hexokinase, like many other kinases, requires Mg2+ for its activity, because the true substrate of the enzyme is not ATP4- but the MgATP2- complex. Mg2+ shields the negative charges of the phosphoryl groups in ATP, making the terminal phosphorus atom an easier target for nucleophilic attack by an –OH of glucose.
Where are hexokinases
- Hexokinase is present in all cells of all organisms. Hepatocytes also contain a form of hexokinase called hexokinase IV or glucokinase, which differs from other forms of hexokinase in kinetic and regulatory properties.
- Two enzymes that catalyze the same reaction but are encoded in different genes are called isozymes.
Preparatory phase of glycolysis step two
Glucose -6-phosphate is converted into fructose-6-phosphate with the help of Mg2+. G10=1.7 kj/mols; The reaction proceeds readily in either direction,as might be expected from the relatively small change in standard free energy
The enzyme phosphohexose isomerase
catalyzes the reversible isomerization of glucose 6-phosphate, an aldose, to fructose 6-phosphate, a ketose.
The PFK-1 enzyme
catalyzes the transfer of a phosphoryl group from ATP
PFK-is
is essentially irreversible under cellular conditions, and it is the first“committed” step in the glycolytic pathway; glucose6-phosphate and fructose 6-phosphate have other possible fates, but fructose 1,6-bisphosphate is targeted for glycolysis.
The PFK-1 reaction
is essentially irreversible under cellular conditions, and it is the first“committed” step in the glycolytic pathway; glucose6-phosphate and fructose 6-phosphate have other possible fates, but fructose 1,6-bisphosphate is targeted for glycolysis.
PFK is considered what
PFK-1 was considered the rate-limiting enzyme, because it was known to be closely regulated by fructose 2,6-bisphosphate and other allosteric effectors.
some bacteria and protists and perhaps all plants have
PFK catalyzes the phosphorylation of fructose-6-phosphate into fructose-1,6-biphosphate also using Mg2+ to convert a ATP into ADP G10=-14.2 Kj/mol
More one PFK-1
Phosphofructokinase-1 is a regulatory enzyme, one of the most complex known.
- It is the major point of regulation in glycolysis.
- The activity of PFK-1 is increased whenever:
- the cell’s ATP supply is depleted
- when the ATP breakdown products, ADP and AMP (particularly the latter), are in excess.
- The enzyme is inhibited whenever the cell has ample ATP and is well supplied by other fuels such as fatty acids.
The activity of PFK-1 is increased when
- the cell’s ATP supply is depleted
- when the ATP breakdown products, ADP and AMP (particularly the latter), are in excess.
The enzyme fructose 1,6 bisphosphate aldolase often called aldolase is
catalyzes a reversible aldol condensation
Fructose 1,6 bisphosphate is cleaved to yield
two different triose phosphates, glyceraldehyde3-phosphate, an aldose, and dihydroxyacetonephosphate, a ketose
Although the aldolase reaction has a strong positive standard free energy change
in the direction of fructose1,6-bisphosphate cleavage, at the lower concentrations of reactants present in cells, the actual free-energy change is small and the aldolase reaction is readily reversible
step 4 of glycolysis
Fructose 1,6-bisphosphate <–> dihydroxyacetone + glyceraldehyde 3-phosphate.
Uses an aldolase enzyme.
Only one of the two triose phosphates formed by aldolase, Glyceraldehyde-3-phasphate can
can be directly degraded in the subsequent steps of glycolysis.
The other product, DHP is rapidly and reversibly converted to
glyceraldehyde 3-phosphate by the fifth enzyme of the sequence, triose phosphate isomerase
Step 5
Dihydroxyacetonephosphate <–> glyceraldehyde 3-phosphate
Uses triose phosphate isomerase enzyme.
Step 5 characteristics
This reaction completes the preparatory phase of glycolysis. The hexose molecule has been phosphorylated at C-1 and C-6 and then cleaved to form two molecules of glyceraldehyde 3-phosphate.
The payoff phase
Remember that one molecule of glucose yields two molecules of glyceraldehyde 3-phosphate; both halves of the glucose molecule follow the same pathway in the second phase of glycolysis. The conversion of two molecules of glyceraldehyde 3-phosphate to two molecules of pyruvate is accompanied by the formation of four molecules of ATP from ADP
The first step of the payoff phase
glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate, catalyzed by glyceraldehyde 3-phosphate dehydrogenase
The acceptor of hydrogen in the glyceraldehyde 3-phosphate dehydrogenase is
is NAD
Because cells maintain only limited amounts of NAD
glycolysis would soon come to a halt if the NADH formed in this step of glycolysis were not continuously oxidized
Step 6
Glyceraldehyde 3-Phosphate + Pi <–> 1,3-biphosphoglycerate.
Uses G3P dehydrogenase enzyme.
NAD+ <–> NADH
step 7
1,3-bisphosphoglycerate + ADP <–> 3-phosphoglycerate + ATP+ mg2+
Uses phosphoglycerate kinase enzyme.
The enzyme phosphoglycerate kinase
transfers the high-energy phosphoryl group from the carboxyl group of 1,3-bisphosphoglycerate to ADP, forming ATP and 3-phosphoglycerate
Steps 6 and 7 are
exothermic together
Step 8
3-phosphoglycerate <–> 2-phosphoglycerate
Uses phosphoglycerate mutase enzyme and Mg2+
2,3 BPG
s initially phosphorylated by phosphoryl transfer from 2,3-BPG, which is required in small quantities to initiate the catalytic cycle and is continuously regenerated by that cycle.
Step 9
2-phosphoglycerate <–> Phosphoenolpyruvate (PEP)
Uses enolase enzyme.
Dehydration reaction (loss of water).
Enolase promotes
reversible removal of a molecule of water from 2-phosphoglycerate to yield phosphoenolpyruvate (PEP)
Step 10
PEP + ADP –> Pyruvate + ATP
Uses pyruvate kinase enzyme + mg2+ and K+.
TCA cycle step one
Oxaloacetate( 4C) + Acetyle CoA( 2C) –> Citrate
Too much citrate can be used to make
Fatty acid steroid synthasis
Citrate to
Isocitrate by enzyme Aconitase
Isocitrate to
a-ketoglutarate by Isocitrate dehydrogenase
a-ketogluterate to
Succinyl CoA by a-ketoglutarate dehydrogenase
A-ketogluterate can be used
for AA synthesis
Succinate to
Fumarate by Succinul dehydrogenase
Malate to
Oxaloacetate by malate dehydrogenase
Oxaloacetate to
PEP by PEP carboxykinase
PEP to either
Glucose of AA
Phosphatase
Dephosphatase in liver and kidneys
More glycogen becomes
Fat
Long chain fatty acids to
–> FA spiral–> Acetyl CoA by B-oxidation
16FA –>
8 Acetyl coA
16FA –>
8 Acetyl coA
Insulin has a
Anabolic function Inhibits fat burning
Acetyl coA–>
lipogenesis–> FAs
Amminoacids–>
Nitrogen pools
Nitrogen pool–>
-Pyruvate
- Acetyl coA
- NH3–> Urea cycle
ATP/AMP:ADP: P ratio is decreased
FA metabolism is stimmulated
Vegans dont eat meat
receptor hit BV and then cholestral can be internalized
Cholesterol is a
Steroid hormone
Endogenous cholesterol synthesis pathway
your body can make Cholesterol
Pentose phosphate pathway will
Reduce Oxidative damage
Too much NADH and FADH then citrate will exit the mitochondria and make
FAT
Citrate is exergonic products or endergonic products –>
products are endergonic
Acetyl coA + oxaloacetate to citrate is
Catabolic and exergonic
A high NADH can
fight Oxidative damage
NADH=
Redox potential elevated
As we age
Increase in NAP+ and FAP2+
Alpha confirmation
OH on bottom
Beta confirmation
OH is on top
Km values indicate how strong
Interaction of molecules
Velocity vs what
Substrate
Vmax is
Maximum velocity of reactions
Km is
is Substrate concentration that is required to make speed to reach 1/2 vmax
lower kM=
high affinity
Higher kM
lower affinity
too much glucose in cells
apoptosis
glucose is important in
regulating osmo
Obligatory glycolysis
Lack of mitochondria= RBC
Glucuronic acid is important in
clearing bilirubin
Heparin is a
Anti-oxidant
there is no heparinized
Serum
Integral proteins
Glycolysalated proteins
Fructose 1-6 Bisphosphatase will influence what
Gluconeogenesis
GLycogen to
Glucose 1 phosphate
UDP gal for
UDP glucose
1- benign form of epimerase deficiency
only in RBC and WBC
transferace form of epimerase defciency
whole body
Glucose UDP to
glycogen-G-G-G glycogen synthase
Epipinephere
Sympathetic nervous system- HR increase- ATP increase– ADP and AMP increase
Glycogen synthase activity is increased if blank is removed
Phosphate
PKA inhibits glycogen synthesis but enhances
Glycogenolysis
regulation of Pyruvate dehydrogenase
-Allosteric regulation
inhibited by ATP, acetyl coA, and NADH
Activated by AMP, CoA, and NAD+
- Covalent regulation
Activated by Dephosphorylation (PD phosphatase)
Inhibited by phosphorylation of E1(pyruvate dehydrogenase) ( by PD kinase activated by ATP)
Pyruvate with enzyme Pyruvate dehydrogenase –>
Acetyl coA with lose of CO2
Only small FA can
be used to go into the mitochondria and make acetyl coA
Pyruvate dehydrogenase complex cofactors
Lipoate, FAD+, and TPP
Pyruvate dehydrogenase complex
E1= real pyruvate dehydrogenase
E2= Dyhydrolipamide transferase
E3= Dihydrolipoamide dehydrogenase= is the dehydrogenase
Thiamine pyrophosphatase is needed in
Oxidative decarboxylation and simple decarboxylation
gluconeogenisis components
Glyceral, AA, and lactate
lactate= to pyruvate
alanine= to pyruvate
glyceral= to glyceraldehyde 3 phosphate
thrid name for Pentose phosphate pathway
Alternative glucose oxidation pathway
Glucose becomes ribose through
hydrolysis
Ribose is used in
Nucleotides and nucleic acids-utilization of pentose
PPP=NADPH=
used in FA and cholesterol synthesis
liver=
lipogenesis FA and cholestral synthesis
Mammary gland
FA storage
NAPDH can be a source of hydrogen for
Oxidized glutathione
Lenghts of survival of cells depend on
Pentose phos pathway
glucose can get into cells by
Glucose transportors
PPP= glucose 6-phosphate-2 pathways
1.) glucose 6 phosphate–> glycolysis–> 2 pyruvate or NADH or 2 ATPs–> lactate dehydrogenase–> Lactate+NAD+
**The second pathway is the Pentose phosphate pathway
2.) 1. glucose 6-phosphate–> Glucose 6 phosphate dehydrogenase–> 2NADP+ to NADPH–> Glutathione reductase–> 3a- 2GSH to GSGS–> 3B. 2GSH–> glutathione peroxidase–> H202 to 2H20
OH- is a strong source of
hemolysis
ROS is built up
Heiz bodies
Pentose phosphate pathway oxidative step one
1.) Glucose 6 phosphate is oxidized with enzyme G6PDH and NADP to NADPH—> 6- phosphogluconolacetate
The pentose phosphate pathway is divided into two steps
Oxidative and non-oxidative
PPP step three oxidative
6-phosphogluconate with enzyme 6-phosphogluconate DH with NADP+, NADPH, CO2—-> Ribulose 5-phosphate
Ribulose-5 phosphate oxidative to
Non oxidative reactions
PPP oxidative step two
6 phosphogluconolactone is hydrolized( h20–>OH+H) with enzyme gluconolactonase —> 6 phosphogluconate.
step one of PPP oxidative in word form
G-6-P is oxidized to 6-phosphogluconolactone by G-6-PDH
- 1 molecule of NADPH is generated by reducing NADP
Step two of PPP oxidative in word form
The lactone is hydrolyzed by a lactonase to 6-phosphogluconate
Step three of PPP oxidative in word form
6-phosphogluconate is oxidatively decarboxylated
by 6-phosphogluonate dehydrogenase to ribulose-5-phophate and CO2
And an additional molecule of NADPH
Step 4,5,6 PPP oxidative in word form
4) Ribulose-5-P Ribose-5-P [Phosphopentose isomerase]DNA and RNA synthesis
5) Unneeded ribose-5-Ps are recycled back to hexose-6-Ps thought a series transketolase & transaldolase- catalyzed reactions
6) The resulting hexose phosphates are either recycled through the pentose phosphate pathway or through glycolysis
Non oxidative PPP
recycled pathway
PPP non oxidative steps
ribose 5 P made and goes to DNA and RNA synthesis
- if we don’t need Ribose 5 P then R5P goes to Glyceraldehyde 3 P in step 6 of Glycolysis
- Fructose 6 P can go to step 2 in Glycolysis
- glucose 6 P can go to step one of glycolysis
Non-oxidative steps of PPPcan be connected to the
glycolytic pathway
activators of TCA enzymes
Substrates, AMP and ADP, and NAD+
Oxaloacetate is really important for gluconeogenesis
Oxaloactate–> PEP–> either AA or glucose
TCA cycle- Pyruvate—> oxaloacetate is catalyzed by what
ATP dependent reaction with pyruvate carboxylase
what activates Pyruvate carboxylase
Biotin and acetyl coA
Muscle response to exercise
Glycogen synthesis decreased,
glycolysis increased
increased degradation
Glycerol phosphate shuttle
1A.(1/2) glucose —> glyceraldehyde 3 phosphate
2A. Glyceraldehyde 3 phosphate with glyceraldehyde 3PDH—> 1,3 BPG
2B. NAD–>NaDH
2C. glycerol 3 phosphate with glycerol 3 PDH–> DHAP
2D. FAD with glycerol 3 PDH–> FADH2
3A- 1,3 BPG–> pyruvate
4A- pyruvate–>acetyl coA
Malate-aspartate shuttle
1A.(1/2) glucose —> glyceraldehyde 3 phosphate
2A. Glyceraldehyde 3 phosphate with glyceraldehyde 3PDH—> 1,3 BPG
2B. NAD–>NaDH
2C. OAA with MDH enzyme—> Malate
2D. malate–>a-ketoglutarate
3A. 1,3 BPG–> pyruvate
4A. Pyruvate–> Acetyl coA
Malate aspartate shuttle and glycerol phosphate Shuttle work under what conditions
Aerobic conditions
The Alanine cycle
Glucose—> 2pyruvate—> alanine muscle
Alanine—> pyruvate—> glucose liver
6atps consumed
Alanine—> NH2–> urea
4atps are consumed
