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IBMS > Metabolism > Flashcards

Metabolism Flashcards

1
Q

Outline the bypass steps for Gluconeogenesis

A

1: Pyruvate -> Phosphoenolpyruvate
2: Fructose 1,6-BP -> Fructose 6-phosphate
3: Glucose 6-phosphate -> Glucose

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2
Q

Glycolysis and gluconeogenesis reciprocally regulated at the level of which enzyme?

A

Phosphofructokinase

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3
Q

Regulation points in glycolysis

A

Hexokinase
= ALLOSTERIC - Feedback Inhibition by product G-6P

Phosphofructokinase 
= ALLOSTERIC
1. ATP
High ATP -> Allosteric site INHIBITION
Low ATP -> Catalytic site ACTIVATION
  1. 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

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4
Q

How lactate removed from body

A

CORI CYCLE

Lactate dehydrogenase: Lactate -> Pyruvate -> Gluconeogenic Pathway

occurs in liver
requires 6 ATPs = oxygen debt

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5
Q

Gluconeogenesis = manufacture of ‘new’ glucose form non-carbohydrate precursors.

What are some Gluconeogenic precursors?

A
  • Glucogenic amino acids
  • Glycerol
    TAG -> FA + Glycerol
    Glycerol -> Dihydroxyacetone phosphate G3P
  • Lactate
    Lactate dehydrogenase: Lactate -> Pyruvate

** CAN NOT produce glucose from FA’s!!!

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6
Q

Diabetes Type 1/2

A

Type 1 - can’t produce insulin (autoimmune destruction of B cells)
Type 2 - tissues resistant to insulin

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7
Q

Anerobic respiration

Pyruvate -> Lactate

produces what useful by product?

A

NAD+

Regeneration of NAD essential - maintains glycolysis in absence of oxygen

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8
Q

FUNCTIONS OF LIPIDS

A

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

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9
Q

chylomicron

A

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)

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10
Q

The classes of lipoprotein

Source:
Function:

A

(all contain characteristic amounts TAG, cholesterol, cholesterol esters, phospholipids and apoproteins)

  1. 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.
  2. 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.
  3. Low density lipoproteins (LDL)
    Source: Formed in circulation by partial breakdown of IDL
    Function: Delivers cholesterol to peripheral tissues
  4. High density lipoprotein (HDL)
    Source: Liver
    Function: Removes “used” cholesterol from tissues and takes it to liver. Donates apolipoproteins to CM and VLDL
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11
Q

What are Triglycerides

A

= 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

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12
Q

How are triglycerides broken down

A

TG broken down by series of lipolytic reactions

Pancreatic lipases digest TGs (small intestine)

Triacylglycerol –Lipase–> Diacylglycerol –Lipase–> Monoacylgylcerol –MAG lipase–> FA + Glycerol

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13
Q

Bile salts

A

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

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14
Q

Chylomicrons

A

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

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15
Q

Breakdown of TGs in adipocytes

A

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
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16
Q

Fatty Acid B Oxidation

A

Location = Mitochondria (matrix)

Reaction sequence

  1. OXIDATION (FAD+)
  2. HYDRATION (H2O)
  3. OXIDATION (NAD+)
  4. 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

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17
Q

Carnitine

A

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.

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18
Q

Oxidation of Polyunsaturated FAs

A
  • 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

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19
Q

Oxidation of odd numbered FAs

A

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)

20
Q

Ketone bodies

A

Can be used by CNS during starvation
= alternative fuel source during fasting or diabetes

  1. FA B-oxidation
    FAs -> Acetyl CoA
  2. Formation of ketone bodies
    Acetyl CoA -> Ketone bodies e.g. Acetone, Acetoacetate
  3. Ketone bodies -> Acetyl CoA
    in Heart muscle, renal cortex and brain cells
  4. Acetyl CoA -> Citric Acid Cycle
  5. 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

21
Q

Diabetic Ketosis

A

ketone bodies form
blood ph drops
coma and death result

22
Q

Amino Acid Metabolism Overview

A

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

23
Q

Oxidative Degradation of AAs

A

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:

  1. AA + α-ketoglutarate ketoacid + Glutamate

** Pyridoxine (vit B6) required as a cofactor for transamination

  1. Glutamate + NAD+ + H2O –Glutamate dehydrogenase–> α-ketoglutarate + NADH + NH4+
  2. NH4+ –UREA CYCLE–> Urea (excreted)
24
Q

Urea Cycle

A

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
25
Q

Point of integration between urea cycle and TCA cycle

A

Arginosuccinate

1* Formed from Citrulline + Aspartate

Aspartate derived from transamination of oxaloacetate

Aspartate Oxaloacetate

2* Arginosuccinate forms Arginine + Fumarate

  • Arginine continues in urea cycle
  • Fumarate enters TCA cycle = TCA cycle intermediate
26
Q

Fatty Acid Biosynthesis

A

Location = Cytosol

  • excess carbohydrate
  • certain AA C skeletons
  • Alcohol
    ==> Can be converted => FAs and stored as TAG (Triacylglyceride)
  • mainly occurs in Liver and Lactating mammary glands (small amount in kidney and adipose tissue)

Energy source = ATP
Reducing agent = NADPH

Starting point = Acetyl CoA (from carbohydrate breakdown)
- contains C=O carbon in oxidised form, aim to reduce all Cs - if molecule contains highly reduced form of C = good E source

**Acetyl CoA from mitochondrion –> Cytosol

ACA produced in mitochondria, excess needs to be transported to cytoplasm for FA synthesis – synthesis and breakdown of FAs occur in separate cellular compartments

FA oxidation - Mitochondria
FA reduction - Cytoplasm

ACP = Acyl Carrier Protein
- large protein, labels Malonyl CoA as destined for FA synthesis

27
Q

Regulation of FA Biosynthesis

A

Occurs at level of:

  • Acetyl CoA Carboxylase *

Inactivated by phosphorylation (action of kinase)

Activated by phosphatase (removes phosphate group)

Promoted by Citrate
Inhibited by Palmitoyl CoA

28
Q

Important FA modification

A

Arachidonic Acid

29
Q

Pentose Phosphate Pathway

A

Location = CYTOPLASM

Provides:

    • NADPH
    • Ribose 5-sugars

PPP = alternative pathway for glucose oxidation (linked to glycolysis&gluconeogenesis), but NOT for ATP synthesis

Glucose 6P -> IRREVESIBLE OXIDATIVE phase

Fructose 6P -> REVERSIBLE NON-OXIDATIVE phase

Glyceraldehyde 3P -> REVERSIBLE NON-OXIDATIVE phase

PPP used to meet the cells demands
- If cell needs lots of NADPH
G6P -> Oxidative phase and glycolytic intermediates renter PPP to generate more NADPH (No glycolysis/CAC occurs)

  • If cell needs some NADPH and ATP
    G6P -> Oxidative phase
    Glycolytic intermediates renter glycolytic pathway
  • If cell needs lots of Ribose 5-Phosphate
    F6P + G3P enter PPP - works backwards to produce Ribose 5-phosphate => Nucleotides
    *Occurs when cell replicating
  • normal cell replication
  • cancer cell
    => High robes 5-phosphate requirements for nucleotide synthesis
30
Q

Pentose Phosphate Pathway

Oxidative Phase

A

=> Production of 2 NADPH

G6P NADPH + … H+ + 6-Phosphogluconate NADPH + Ribulose 5-phosphate (C5) + CO2

CO2 => exhaled
NADPH => reducing agent e.g. in FA biosynthesis
Ribulose 5P => Non-oxidative phase of PPP

31
Q

Pentose Phosphate Pathway

Non-oxidative Phase

A

3 Ribulose Phosphates => 2 Fructose 6-Phosphates + 1 Glyceraldehyde 3-Phosphate => Feedback into glycolytic/gluconeogenic pathway

32
Q

ETC and Oxidative Phosphorylation

A

Location = Mitochondria Cristae - highly folded => Increases SA for oxidative phosphorylation

Summary:

4 different complexes in ETC receiving either NADH or FADH2 generated in TCA cycle/glycolysis

E-‘s moved through complexes via a series of e- carriers to ultimately generate H2O from O2

Associated with the movement of e-‘s is the extrusion of H+ ions into intermembrane space => proton gradient

ADP regulates oxidative phosphorylation -> main regulator of TCA cycle

33
Q

Electron Carriers in ETC

A
  • Coenzyme Q
    Q (oxidised) + e- + H+ ——-> QH2 (reduced)
    e-s generally added to oxygen groups
  • Flavin mononucleotide (FMN)
    FMN (oxidised) + 2e-s + 2H+ —> FMNH2 (reduced)
    nitrogen groups accept e-/H+
  • Fe-S clusters
    Fe3+ + e- Fe2+
    shuttling between oxidation states also a means of carrying e-‘s through ETC

Fe present in cytochromes (=haemproteins)

34
Q

Chemostatic Hypothesis

A

Proton motive force = Chemical gradient (change in pH) + Charge gradient

35
Q

ATP Synthase

A

ATP Synthase - Rotational Catalysis

Proton motive force causes a proton to enter cytoplasmic half channel from inter membrane space. Each proton follows a complete CLOCKWISE ROTATION of the C ring, and exits through the other half channel into the matrix. Energy of rotation used to synthesis ATP.

36
Q

Glycerol-3-phosphate shuttle

A

(muscle)

pair of e-s transferred from NADH to dihydroxyacetone phosphate (glycolytic intermediate) -> glycerol 3-phosphate

G3P reoxidises to DP on the outer surface of inner mitochondrial membrane by a membrane bound isozyme of G3P dehydrogenase.

E- pair from G3P transferred to an FAD prosthetic group in this enzyme to form FADH2. Reduced flavin transfers it’s e-s to electron carrier Q, then enters respiratory chain as QH2.

NB: FADH2 less e. rich than NADH -> 1.5 ATP .’. NADH generated in glycolysis less E. rich than NADH generated in TCA cycle

37
Q

Malate-aspartate shuttle

A

(liver and adipose tissue)

under some circumstance these shuttles can operate in energy neutral terms - not always energy loss associated with use of shuttles to transport reducing equivalents

38
Q

ATP Translocase

A

ADP (cytoplasmic) binds to the translocase causing an allosteric change -> eversion .’. ADP released into the matrix.
ATP then binds -> eversion releasing ATP into the cytoplasm

39
Q

Inner mitochondrial membrane Permeability

A

Inner mitochondrial membrane = IMPERMEABLE
to NAD+/NADH and ADP/ATP

NAD+/NADH -> transported by SHUTTLES into mitochondrial matrix
E.g: Glycerol-3-phosphate shuttle
Malate-aspartate shuttle

ADP/ATP -> transported by TRANSLOCASES into mitochondrial matrix
E.g: ATP translocase

Transporters used to transport substances across inner mitochondrial membrane - 40 transporters encoded in human genome E.g ATP-ADP translocate, Phosphate carrier (OH-Phosphate)

40
Q

Glycogen Breakdown

A

Glycogen (n residues) + Pi Glucose 1-phosphate + Glycogen (n-1 residues)

Glucose 1-P = more E.rich than glucose

41
Q

Glycogen Phosphorylase

A

Promoted by:

  1. Adrenaline (muscle &liver)
  2. Glucagon (liver only)

Stops cleaving when within 4 residues of a branch point .’. 2 additional enzymes required for Glycogen catabolism

1 - enzyme transfers 3 glucose units to end of glycogen molecule
2 - enzyme cleaves/hydrolyses off the single glucose unit remaining
=> Phosphorylase can start again
.’. Glycogen breakdown generates mainly G1P with some glucose (single hydrolysed residues)
ratio = 8:1

42
Q

Fate of G1P & Glucose in LIVER

A

Glycogen => G1P -> G6P -> Glucose -> released into blood to maintain b.glucose levels

43
Q

Fate of G1P & Glucose in MUSCLE

A

Glycogen => G1P-> G6P
Glycogen => Glucose -> G6P

G6P => Glycolysis in muscle to generate ATP

NB: Unlike liver cell, muscle doesn’t have glucose 6-phosphatase .’. can’t convert G6P -> glucose
.’. G6P trapped in muscle cell for use in glycolysis => ATP production

44
Q

Regulation of Glycogen Metabolism

A

deficient glucose -> glycogen metabolism
excess glucose -> glycogen synthesis

2 processes = reciprocally controlled by hormones & allosteric control

AMP => ALLOSTERICALLY stimulates glycogen breakdown
ATP => inhibits glycogen breakdown

45
Q

Regulation of Glycogen Metabolism:

Hormonal control by glucagon and adrenaline

A

=> glycogen breakdown stimulated, synthesis inhibited

Adrenaline & glucagon = Primary messenger
- bind membrane receptors => conformational change that is transmitted throughout cell => activation of cAMP

cAMP = Secondary messenger
=> AMPLIFICATION CASCADE
- catalysts (enzymes) activate other catalysts (enzymes) .’. only need one hormone molecule to activate thousands/millions of glycogen phosphorylase => large glycogen breakdown

46
Q

Regulation of Glycogen Metabolism:

Hormonal control by insulin

A

Insulin released when blood glucose levels are elevate e.g. after a meal, to lower blood glucose to 5 mmol/L
=> glycogen breakdown inhibited, glycogen synthesis stimulated

Insulin receptor = Tyrosine Kinase
=> De-phosphorylation of glycogen synthase (activates enzyme) and glycogen phosphorylase (inactivates)

glycogen synthase inactivated by phosphorylation
glycogen phosphorylase activated by phosphorylation

47
Q

Glycogen Synthesis

A

Surplus glucose -> glycogen = glycogenesis
Occurs in cytoplasm of liver & muscle cells

Glucose -> Glucose 6-phosphate Glucose 1-phosphate -> UDP-Glucose

UDP-Glucose + Glycogen (n residues) —Glycogen synthase—> UDP + Glycogen (n+1 residues)

Glycogen synthase promoted by:

  • Insulin
  • G6P (+ve regulation)

Formation of branches
- branching enzym transfers a block of glucose units from non-reducing terminal of a glycogen polymer to a more interior site i.e. an alpha 1-4 linkage is broken and an alpha 1-6 linkage is formed..

Deficiency of branching enzyme => liver failure and death in first year of life = Anderton’s disease

IBMS (3 decks)

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