SEMINAR WEEK 4 Flashcards
How is glucose transported into the cells?
FACILITATED DIFFUSION:
- extracellular glucose binds to transporter–>alter conformation–>facilitated diffusion
- glu concentration gradient
- Glu transporters 1–>5 (tissue speciifc expression)
- 1=ery (most tissues)
- 4= muscle , adipose
COTRANSPORT- sodium and atp dependent
- happens in spithelial cells of intestine, renal tubules, choroid plexus
- energy requiring: glucose again conc gradient
- NA down electrochemical gradient
- rquires uptake of NA+ the tranportter is a sodium dependnet glucose cotransporter
first regulatory enzyme in glycolysis
HEXOKINASE/GLUCOKINASE
- glu phsophorylation–>glu-6-phos
hexokinase:’
- regulatory
- all tissues not liver
- broad specificity-several hexoses
- inhibited by glu-6-p and high ration of atp/adp
- low Km–>lower glu lvl
glucokinase:
- liver and B cells of the pancreas
- not inhibited by glu-6-p
second regulatory enzyme in glycolysis:
PHOSPHOFRUCTOKINASE 1
fru-6-p–>fru-1,6-bis-p
- most imp regulatory step
Regulation - high atp and citrate->inhibition
- low amp->activation
regulaiton by fru-2,6-bis-p - acitvat pfk 1
- inhibit fru-1,6-bisphosphatase (neogenesis)
what do we get form the second phase
4, atp, 2 nadh, 2 pyruvates (3C) molecules from one glu (6C)
third regulatory enzyme of glycolysis
PYRUVATE KINASE
phosphoenolpyruvtae->pyruvate
feed forwrads, regualtion:
liver–>fru-1,6,bis-P activate PK- (not in muscles)
covalent modification:
- phosphorylation->cAMP dependent protein kinase
high glucagon->high camp–>phosphorylation of PK->inactibe
-dephosphorylation: phosphatase->Pk acitve -insulin
Conversion of pyruvate to lactate
- anaerobic glycolysis
- reduction to lacate is major fate for pyruvate in tissues poorly vascularized: lens, cornea, kidney medulla, or in RBC that lacks mitochondria
FORMATION IN muscles
excersizing skeletal muscle, NADH prduction(by glyceraldehyde-3-p DH)–>exceed oxidative capacity of the ETC.–>elevated NADH/NAD+ratio favouring the reduction of pyruvate to lactate.
When intense ecxersice–> lactate accumulates in muscle–>drop in intracellular ph–>cramp. Much if this lactate diffuses into bloodstream and can be used by liver to make glucose
LACTATE CONSUPMTION/UTILIZATION
- Lac consumption – alternative metabolic substrate for heart
- LD metabolic function
liver: a) Lac → Pyr → Glu (gluconeogenesis) (high in low Glu)
b) Lac → Pyr → Krebs cycle (low)
myocard: Lac → Pyr → Krebs cycle (alternative source of energy)
heart: lactate–>carbondioxide and water via the TCA cycle
-
energetic yield of glycolysis: anaerobic
- Anaerobic glycolysis
Glu + 2 Pi + 2 ADP → 2 Lac´ + 2 ATP + 2H2O
a) ATP production
- 2 molecules ATP on 1 molecule of Glu
- small energetic yield
- cells and tissues without or very limited amount of MIT → Ery, Leu, kidney medulla
b) NADH production
- no net NADH yield
- 1x NADH + (glyceraldehydedehydrogenase) - production
- 1x NADH – (lactate dehydrogenase) - consumptio
energetic yield of glycolysis: aerobic
- Aerobic glycolysis
Glu + 2 Pi + 2 NAD+ + 2 ADP → 2 Pyr´ + 2 ATP + 2 NADH + 2 H+ + 2 H2O
- 2 ATP consumption (phosphorylation in the first phase of glycolysis)
- 4 ATP production (2 ATP per one triose)
- net yield = 2 ATP
- 2 x NADH → 2,5 ATP per one NADH
Comparison of the yield
from Glu after lactic acid production:
glycolysis: 2 ATP (substrate level)
Glu oxidation to CO2 and H2O in aerobic conditions:
glycolysis + citrate cycle + terminal oxidation: 30- 32 ATP !!!
Main pathway for energy production- brain, muscle, heart, kidney!!!
glycolysis reg
- short-term (min or hrs)
- allosteric activation/inhibition
- phosphorylation/dephosphorylation - long-term (hrs – days)
- hormones (insulin+ , glucagon - )
- 10 – 20 x increase of the enzymatic activity - regulatory enzymes
a/ hexo/glucokinase
b/ phosphofructokinase 1
c/ pyruvate kinase
what is lactic acidosis
increase of NADH/NAD+ ratio->inhibition of pyruvate DH
where does gluconeogenesis happen
as the brain, erythrocytes, kidney medulla, lens
and cornea of the eye, testes, and exercising skeletal muscle,
require a continuous supply of glucose as a metabolic fuel.
gluconeogenic precursors
Precursors
1. Lactate (anaerobic glycolysis, RBC, muscle):
- aminoacids (muscle proteins,
or glutamin): hydrolysis by tissue protein, major source of glucose during fast. metabolism generate a-keto acids like pyruvate thats converted to glucose, or a-ketoglutarate that enter TCA and forom oxoloacetat for PEP - glycerol (adipose): form hydrolysis of TAG and delivered by blood to liver.
first regulatory enzyme of gluconeogenesis
PYRUVATE KINASE: PEP->PYR
second regulatory enzyem in glyconeogenesis
dephos of fru-1,6 bis-p
- regulatory step:
a) cell energetic status ↓ AMP+; ↑ATP+
↑ AMP
b) regulation by Fru-2,6-bisphosphate
- allosteric inhibition of fructose 1,6-bisphosphatase
3rd regulatory enzyme in glconeogenesis
dephos of glu-6-p
All enzymes are exclusively localized:
Liver (90%), kidney medulla (10%)
Intestinal mucosa (10% !!!
substrates for gluconeogenesis
Substrates for gluconeogenesis:
1. lactate- immediate substrate
Cori cycle – Glu (liver) → blood → exercising muscle, RBC → lactate
(blood) → liver (gluconeogenesis)
- Amino acids and α-ketoacids from muscle proteins send as ALANINE
- Glu-Ala cycle:- starvation- glucagon
i)Glucogenic AA – Ala, Ser, Gly, Cys, Thr (pyruvate);
Asp (oxalacetate); Glu (alfa-ketoglutarate)
ii) pyruvate, oxalacetate, alfa-ketoglutarate - glycerol- prolonged starvation – degradation of adipose in conn. tiss.
- product of lipolysis (TAG) in the adipose tissue by Hormone sens. lipase
- transport into the liver- cortisol
- phosphorylation → glycerol-P (oxidation) → dihydroxyacetone-P
regulation of gluconeogenesis
Regulation of gluconeogenesis:
➢ simultaneous inhibition of enzymes of
glycolysis and activation of gluconeogenesis!
1. Pyruvate → PEP
Fosfoenolpyruvatecarboxykinase
- Induction (glukagon, adrenalin, cortisol)
- inhibition (insulin)
2. Fructose-1,6-P → Fructose-6-P
Fructose-1,6-bisphosphatase – inhibition
(fructose-2,6-P)
3. Glucose-6-P → Glucose
Glucose -6-phosfatase – induction by fastin
cori cycle
The Cori cycle, also known as the lactic acid cycle, is a metabolic pathway that describes the interconversion of glucose and lactate between tissues, particularly between muscle and liver. It plays a crucial role in maintaining blood glucose levels and recycling lactate produced by muscles during anaerobic glycolysis.
The Cori cycle allows for the conversion of lactate produced in muscles under conditions of high energy demand or oxygen shortage (anaerobic conditions) back into glucose in the liver. This glucose can then be released into the bloodstream to supply energy to other tissues, including muscles, where it can be utilized during subsequent physical activity. The cycle helps in the maintenance of blood glucose levels and contributes to the efficient utilization of lactate as an energy source, preventing the buildup of excess lactate in the body.
glucose-alanine cycle
Glucose – alanine cycle
- anaerobic glycolysis → lactate and alanine, later muscle proteolysis (cortisol)
- blood: alanine is transfered to the liver
- liver: a/ ammonia is released → converted to urea- excretion via kidneys
b/ pyruvate → gluconeogenesis → glucose
- less productive process than the Cori cycle
- Side product - urea
- removal of the urea is energy-dependent → total ATP production is lower!!
regulation of gluconeogenesis
Regulation of gluconeogenesis
* Glucagon – stimulation of gluconeogenesis
a) decreases level of Fru-1,6-bisphosphate which leads to
→ activation of fructose 1,6-bisphosphatase (gluconeogenesis)
→ inhibition of phosphofructokinase 1 (glycolysis)
b) covalent modification of the enzymatic activity
- ↑ cAMP → active protein kinase A → inactive pyruvate kinase (P)
=> phosphoenolpyruvate accumulation
* Cortisol-stimulation of muscle proteolysis- sarcopenia
+cachexia
* Cortisol stimulated of adipose TAG hydrolysis- cachexia
* Substrate availability
↓ insulin → mobilization of proteins → glucogenic AA
* Allosteric activation by acetyl-CoA
↑ acetyl-CoA → stimulation of pyruvate carboxylase during prolonged
starvation (liver
