Metabolism Flashcards
(47 cards)
Outline the bypass steps for Gluconeogenesis
1: Pyruvate -> Phosphoenolpyruvate
2: Fructose 1,6-BP -> Fructose 6-phosphate
3: Glucose 6-phosphate -> Glucose
Glycolysis and gluconeogenesis reciprocally regulated at the level of which enzyme?
Phosphofructokinase
Regulation points in glycolysis
Hexokinase
= ALLOSTERIC - Feedback Inhibition by product G-6P
Phosphofructokinase = ALLOSTERIC 1. ATP High ATP -> Allosteric site INHIBITION Low ATP -> Catalytic site ACTIVATION
- Glucose
High glucose -> drives rxn forwards by coordinate regulation
High glucose -> isomer F-2,6-BP, as not a glycolytic intermediate cell alerted to high glucose concentration and F-2,6-BP activates PFK to produce F-1,6-BP
=> F-2,6-BP increases PFK reaction velocity
Pyruvate kinase
= COVALENT MODIFICATION by phosphorylation
stimulated by F-1,6-BP
inhibited by ATP
less active in phosphorylated form
Pyruvate Dehydrogenase (Pyruvate-> Acetyl CoA) = COVALENT MODIFICATION by phosphorylation
phosphorylation -> Inactivation
high energy charge -> inhibition
low energy charge -> activation
How lactate removed from body
CORI CYCLE
Lactate dehydrogenase: Lactate -> Pyruvate -> Gluconeogenic Pathway
occurs in liver
requires 6 ATPs = oxygen debt
Gluconeogenesis = manufacture of ‘new’ glucose form non-carbohydrate precursors.
What are some Gluconeogenic precursors?
- Glucogenic amino acids
- Glycerol
TAG -> FA + Glycerol
Glycerol -> Dihydroxyacetone phosphate G3P - Lactate
Lactate dehydrogenase: Lactate -> Pyruvate
** CAN NOT produce glucose from FA’s!!!
Diabetes Type 1/2
Type 1 - can’t produce insulin (autoimmune destruction of B cells)
Type 2 - tissues resistant to insulin
Anerobic respiration
Pyruvate -> Lactate
produces what useful by product?
NAD+
Regeneration of NAD essential - maintains glycolysis in absence of oxygen
FUNCTIONS OF LIPIDS
Major components of cell membranes.
Required to solubilise fat soluble vitamins
Biosynthetic precursors (e.g. steroid hormones from cholesterol)
Protection (e.g. kidneys are shielded with fat in fed state)
Insulation
chylomicron
Triacylglycerol + cholesterol + phospholipid + proteins form a lipoprotein complex called a chylomicron which transports the lipids in the circulation.
(Lipids are insoluble in plasma. In order to be transported they are combined with specific proteins to form lipoproteins)
The classes of lipoprotein
Source:
Function:
(all contain characteristic amounts TAG, cholesterol, cholesterol esters, phospholipids and apoproteins)
- Chylomicrons (CM)
Source: Intestine
Function: Transport dietary TAG to the adipose tissues where it can be stored as fat or to muscles where the constituent fatty acids can be used for energy. - Very Low Density Lipoproteins (VLDL)
Source: Liver
Function: Transport endogenously synthesised TAG to the extra hepatic tissues where it can be stored as fat or to muscles where the constituent fatty acids can be used for energy. The cholesterol is delivered to extra hepatic tissues once VLDL has been metabolised to LDL. - Low density lipoproteins (LDL)
Source: Formed in circulation by partial breakdown of IDL
Function: Delivers cholesterol to peripheral tissues - High density lipoprotein (HDL)
Source: Liver
Function: Removes “used” cholesterol from tissues and takes it to liver. Donates apolipoproteins to CM and VLDL
What are Triglycerides
= Highly concentrated energy store
Formed by esterification of FAs to glycerol at each of the hydroxyl groups
Reside in adipocytes (fat cells) = energy store
source = dietary lipids
How are triglycerides broken down
TG broken down by series of lipolytic reactions
Pancreatic lipases digest TGs (small intestine)
Triacylglycerol –Lipase–> Diacylglycerol –Lipase–> Monoacylgylcerol –MAG lipase–> FA + Glycerol
Bile salts
Made and stored in gall bladder e.g. glycocholate
Contain a hydrophobic structure and an ionic structure -> physiological detergents - act to dissolve and emulsify TGs in the small intestine & make them accessible to pancreatic lipase
Bile Salts emulsify dietary TGs & then lipase act on TG micelles
Chylomicrons
Triacylglycerols broken down by lipase into monoacylglycerols + FAs which cross gut wall
Inside mucosal cell reassembled into TGs
TGs combine with other lipids and proteins –> Chylomicrons –> Lymph system –> Adipocytes
Chylomicrons = protein-lipid complexes used to transport lipid in the blood stream and eventually into lymphatic system
Breakdown of TGs in adipocytes
Hormones Sensitive Lipase (HSL) hydrolyses TGs –> FAs (energy rich) + Glycerol (metabolised by glycolysis - converted into glycolytic intermediates DP & G3P + production of NADH)
HSL main regulators:
- Glucagon
- Adrenaline
=> Activation of 7TM membrane receptor –> elevation of cAMP (cyclic AMP) = secondary messenger - controls activity of protein kinases (=> +Pi)
Protein kinase A posphorylates: Perilipin + HSL=> activation of lipolysis
Adipocyte TG
- –> Glycerol -> Liver cell: Glycolysis ->Pyruvate / Gluconeogenesis -> Glucose
- –> FAs -> other tissues: FA oxidation -> Acetyl CoA -> TCA cycle -> CO2 + H2O
Fatty Acid B Oxidation
Location = Mitochondria (matrix)
Reaction sequence
- OXIDATION (FAD+)
- HYDRATION (H2O)
- OXIDATION (NAD+)
- CLEAVAGE /Thiolysis (HS-CoA)
FAs degraded by repetition of this reaction sequence
Activated FA (Activated Acyl CoA) –>–>–>–> Activated Acyl CoA (shortened by 2C atoms) + Acetyl CoA (2C)
Activated Acyl CoA renters cycle
Acetyl CoA -> TCA cycle => 2 NADH, 1 FADH, 1 GTP
NB: FAs activated as CoA derivatives via ATP
FA + ATP + HS-CoA => Acyl CoA + AMP
Acyl CoA needs to be transported to mitochondrial matrix for B-oxidation
Translocase transports FA-carnitine -> m.matrix
Acyl CoA + carnitine -> Acyl Carnitine (has translocase transporter) + HS-CoA
Carnitine
Combines with Acyl CoA (activated FAs) to transport them across membrane into mitochondrial matrix for B-oxidation as Acyl Carnitine.
Converted back into Acyl CoA once in matrix.
Oxidation of Polyunsaturated FAs
- Requires ISOMERASE and REDUCTASE
Isomerase => trans configuration = intermediate in B-oxidation
Reductase => reduces FA so less double bonds using NADPH
Unsaturated FA oxidation:
Odd numbered double bonds -> ISOMERASE
Even numbered double bonds -> ISOMERASE + REDUCTASE
Always require isomerase - unsaturated FAs must be in TRANS configuration for B-oxidation
Oxidation of odd numbered FAs
Final round of B-oxiation =>
C2 Acetyl CoA + C3 Propionyl CoA
Propionyl CoA converted to TCA cycle intermediate Succinyl CoA (vit B12 dependent, require ATP)
Ketone bodies
Can be used by CNS during starvation
= alternative fuel source during fasting or diabetes
- FA B-oxidation
FAs -> Acetyl CoA - Formation of ketone bodies
Acetyl CoA -> Ketone bodies e.g. Acetone, Acetoacetate - Ketone bodies -> Acetyl CoA
in Heart muscle, renal cortex and brain cells - Acetyl CoA -> Citric Acid Cycle
- Oxidative Phosphorylation
NB:
Ketone bodies formed by condensation of 3 x Acetyl CoA molecules
Ketone bodies converted back to Acetyl CoA as energy source:
Acetoacetate –CoA transferase–> Acetoacetyl CoA –Thiolase + CoA–> 2Acetyl CoA
Diabetic Ketosis
ketone bodies form
blood ph drops
coma and death result
Amino Acid Metabolism Overview
Proteins digested -> AAs in GI tract
Proteins tagged for degradation (normal protein turnover) with UBIQUITIN
Ubiquitin tagging = signal for proteosome to digest proteins into constituent amino acids
AA
- left intact for biosynthesis (AAs = precursors for other biomolecules)
or
-> Amino groups => Nitrogen disposal by UREA CYCLE => Oxidative degradation of AAs (Hepatic (liver): mitochondrial)
-> Carbon skeleton
=> FA synthesis
=> Glucose or glycogen synthesis
=> Cellular respiration => Catabolism of AA carbon skeleton in TCA cycle
Oxidative Degradation of AAs
GLUTAMATE = Initial NH4 acceptor
Each AA has it’s own aminotransferase
Amino Acid –Aminotransferase–> Glutamate (=universal nitrogen acceptor) –Glutamate dehydrogenase–> NH4+
Glutamate dehydrogenase releases NH4 from glutamate = OXIDATION (removal of H with associated electrons)
Overall:
- AA + α-ketoglutarate ketoacid + Glutamate
** Pyridoxine (vit B6) required as a cofactor for transamination
- Glutamate + NAD+ + H2O –Glutamate dehydrogenase–> α-ketoglutarate + NADH + NH4+
- NH4+ –UREA CYCLE–> Urea (excreted)
Urea Cycle
1st committed step requires energy investment => 2ATP (used to synthesise carbomyl phosphate)
.’. Regulation of urea cycle at first committed step!
1st committed step of urea cycle occurs in mitochondrion, L-Citrulline is then synthesised and transported out of mitochondrion.
CO2 + NH4+ => Carbamoyl Phosphate \+ Orthinine => Citrulline \+ Aspartate => Arginosuccinate => Fumarate + Arginine Arginine => UREA + Orthinine Orthinine + Carbomoyl-P => Citrulline
