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Cell Metabolism and Metabolic Control > Carbohydrates > Flashcards

Carbohydrates Flashcards

1
Q

How do control mechanisms differ between organisms?

A

Basic features are similar; complexity of these varies to match the environment

e. g. bacteria continually adapt due to a short lifetime, humans less so
e. g. carbon cycle, cells working in a paracrine, autocrine or exocrine manner to best cope with environmental demands

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2
Q

What is flux?

A

Direction of carbon skeletons - determines their fate, e.g. pentose phosphate, ATP production etc

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3
Q

Where are all enzymes for glucose handling?

A

Within the cell - these regulate fate of glucose and control net direction of movement

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4
Q

Futile cycle?

A

The energy required to make G6P with no return; this is coordinated to produce useful precursors for energy production further down to recoup these losses

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5
Q

Function of glycolysis and gluconeogenesis

A

ATP from glycolysis (substrate level phosphorylation) and CAC (mitochondria and some cells, ox phos)
Storage glycogen - muscle and liver
FA and TAG synthesis
Glycolytic cells i.e. those that lack mcs like RBCs, kidney, or that cannot transport FAs e.g. neurones
Other sugar production

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6
Q

What metabolites in glycolysis cross over with other pathways?

A

G6P
Pyruvate
Acetyl CoA

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7
Q

Glucose transporters

A

GLUT1-12, specific for tissues/sugar type
GLUT4 = major, in muscle
GLUT2 = liver
Each is regulated differently, but main response is the insulin, especially GLUT4

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8
Q

Structure of GLUTs?

A

12 transmembrane proteins forming central core to let glucose through
Tissue specific expression through promoter-regulated control; myocyte enhancer factor MEF-2 binds thyroid hormone receptor, dimerises, and binds to promotor of GLUT4
(time-specific control)

Developmental control - GLUT1 switches to GLUT4 from foetal to neonatal (newborn) muscle

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9
Q

Regulation of GLUTs?

A

Exist in pools in the cells, moved to and from the membrane in vesicles. e.g. GLUT4 in specific vesicles moved to membrane in response to insulin
Endosomal GLUT1/4 vesicles moved to membrane by muscle contraction (calcium signalling) or anoxia (low O2)

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10
Q

Varberg effect?

A

Anoxia means electron transport chain can’t be used = glycolysis must be used for energy. The switch to this is the Varburg effect

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11
Q

Overall glucose uptake increase due to:

A

Regulation after food; insulin directs excess to adipose tissue for storage as TAGs
Energy production regulation; exercise/anosmia to fuel movement or replenish glycogen stores

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12
Q

GLUT2

A

Liver-specific, no regulation of movement to/from plasma membrane
Dependent on glucose conc in blood stream, and is fully reversible

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13
Q

OVERALL REG OF UPTAKE

A

GLUT tissue-specificity
Compartmentalisation of GLUT within cell
ER partitioning (??)
Subcellular transport e.g. into mitochondria
Concentration gradients in absence of transporters

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14
Q

Glucose - G6P?

A

Hexokinases phosphorylate to form G6P, G6P-phosphase reverses
G6P is an allosteric inhibitor of HxK, via feedback inhibition

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15
Q

Control of phos/dephosphorylation?

A

Enzyme presence/absence
Tissue-specific isoenzymes
State - G6Pase increases activty in starved states, hexokinase massively drops

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16
Q

Hexokinase isoenzymes?

A

I (A), II (B), III (C)

IV (D) = glucokinase, liver, high affinity

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17
Q

Glucokinase?

A

Saturates at 10-15mM of glucose, greater than physiological glucose concentration so can sense excess/lack
Present in liver, where blood from intestines first arrives
Also in pancreatic B cell, where insulin is released

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18
Q

Regulation of glucokinase?

A

Glucokinase gene: complex promoter binds many elements for net effect
Transcription: insulin up via SREBP-1c, CREB down via glucagon – PKA
GK protein - compartmentation with GRP
Degradation - stimulated by glucagon

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19
Q

Glucokinase regulatory protein

A

Glycolysis = in cytosol
GK localises to cytosol in fed states
When not needed, medium-term control occurs through nuclear sequestration by GRP, binding GK
F6P, further down pathway from G6P, activates GRP to sequester GK in feedback inhibition
Insulin and F1P inhibit GRP

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20
Q

Regulation of G6Phosphatase

A

4 subunits, translocases T1-3 and a catalytic G6Pase unit
T1 = entry of G6P
T3=exit of glucose
T2-exit of P
Complexes hold catalytic unit in an active conformation

G6Pase unit - FKHR and Foxo1a needed for transcription
Foxo1a dephos via insulin signalling = inactivates transcription = glycolysis

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21
Q

F6P - F16BP

A 
Forward = phosphofructokinase PFK, all cells
F16BPase = glucogenic tissues e.g. liver, muscle
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22
Q

Phosphofructokinase control

A

Allosteric control = ATP and citrate inhibit
AMP/Pi and F26BP stimulate

Isoenzymes:
PFK-1 = F6P-F16BP
PFK-2 = F6P-F26BP OR reversal

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23
Q

Role of F26BP?

A

Stimulates PFK-1

Inibits F16BPase

24
Q

PFK-2?

A

Forms F26BP
Bifunctional - single chain with N terminal PFK-2 activity
C terminal F26BPase activity to reverse

Phosphorylation of either end can fold/unfold and expose that activity to bias activity

This can also have isoforms within itself - alternative splicing varies in cells/cell types to change activity ratio

25
Q

PFK-2 isoforms and regulation?

A

L-type - PKA phosphorylates, activated by glucagon, inhibiting PFK-2 activity to favour F26BPase

H and i type - AMP-activated PK phosphorylates, by hypoxia and exercise, to favour PFK-2 activity

Long-term, i-type induced transcriptionally by hypoxia
L-type decreased in starvation and diabetes

26
Q

Phosphoenolpyruvate (PEP) – pyruvate cycle

A

PEPCK: oxaloacetate — PEP
PK (pyruvate kinase): PEP — pyruvate
PC (pyruvate carboxylase): Pyr — Oxaloacetate
Pyruvate dehydrogenase: Pyr — Acetyl CoA

27
Q

Pyruvate kinase

A

Cytosolic, encoded by two genes, two transcripts from each for isoenzymes:
PKL;
R protein, in RBCs
L protein, in liver, kidney

PKM;
M1 protein, in muscle, heart, brain
M2 protein, minorly in most tissues, major in tumours, foetal form too

28
Q

Regulation of R and L isoenzymes?

A

Feedforward activation by F16BP
Feedback inhibition by ATP

Inhibited also by AAs, PKA via glucagon, to favour amino acid conversion to glucose in starvation

SREBP-1c linked to L form long-term control via genes

29
Q

Acetyl CoA (acoa) fates?

A

Sterols
Ketones
FAs, triglycerides, phospholipids: oxidised in CAC for ATP

30
Q

Oxaloacetate fates?

A

Glucose
Transamination for AAs
CAC intermediate replenishing

31
Q

Pyruvate dehydrogenase (PDH) regulation

A

Forms acCoA
Regulatory or catalytic
Phosphorylation by PDH kinase = inactive
Dephos by PDH phosphatase = active

32
Q

PDH kinase and phosphatase regulation

A

KINASE
By metabolites: activated by acCoA and NADH, products of PDH i.e. feedback inhibition
acCoA also from FA oxidation = cross talk
Inhibited by ADP

PHOSPHATASE
Insulin signalling activates
Also coordinates with FA use in starvation

33
Q

Glucose-FA cycle

A

Preferential use of FAs for ATP

FAs = acCoA = CAC = ATP
Citrate from CAC = inhibits PFK to stop F6P transfer

acCoA inhibits PDH, preventing pyruvate – acCoA (direct to other use)

34
Q

Pyruvate carboxylase (PC)

A

Required for glucose synthesis in the liver (pyruvate – oxaloacetate precursors)

Mitochondrial localisation and activity - single gene with isoforms produced by tissue-specific alternative promoters

Allosterically activated by acCoA

35
Q

Pyruvate carboxylase isoenzymes?

A

Proximal promoter use: liver, adipose tissue for inducible transcription
Increased by glucagon and glucocorticoids
Decreased by insulin

Distal promoter: kidney, constitutive transcription

36
Q

Phosphoenolpyruvate carboxykinase (PEPCK)

A

Cytosolic (inducible) and mitochondrial isoforms from two separate genes

Transcriptional regulators: Foxo1, Creb, SREBP, HND etc
SREBP-1c inhibits in fed state
CREB, nuclear receptor upregulate in starvation

37
Q

PEPCK isoforms and regulation

A

Cytosolic: conversion of AA to glucose, inducible
Mitochondrial: lactate recycling (Cori cycle), consitutive

38
Q

Pentose phosphate pathway

A

Usually less than 10%, 5-50% of glucose catabolism
In cells undergoing:
active cell division e.g. tumours
active FA synthesis e.g. adipocytes
Circular pathway;
G6P – 6 phosphogluconate – ribulose 5 phosphate

39
Q

Function and regulation of pentose phosphate pathway

A

Produces:
NADPH - for biosynthetic pathways e.g. FA
Ribose sugars - nucleotides e.g. in dividing cells
Catalysed by two dehydrogenases, G6PDH/6PGDH, regulated by gene transcription of each

40
Q

Other sugars?

A

Fructose – F1P by fructokinase in the liver, enters glycolysis
Lactose – galactokinase, for glucose and galactose

41
Q

Glycogen synthesis

A

Built on a fixing protein, localisation of which controls place and amount

Addition of UDP-glucose to glycogenin sequentially = glycogen, using UTP and a number of synthases/branching enzymes

42
Q

Glycogen breakdown

A

Addition of phosphate to C1 = G1P, isomerised by phosphoglucomutase to G6P

Sequential clipping of sugar residue bonds with inorganic phosphate by glycogen phosphorylase and debranching enzymes

43
Q

Complexes in glycogen turnover (7)

A 
Glycogenin and other backbone proteins
Enzymes for synthesis
Enzymes for breakdown
Regulatory protein kinases
Regulatory protein phosphatases e.g. PP-1G
Cytoskeleton interactions
Glycogen storage diseases
44
Q

Glycogen regulation

A

Storage sites/amounts differ

Most cells = small amounts, short term fuel reserve
Muscle - 200g, longer, in absence of G6P or oxygen
Liver - 70g, in starvation for tissues with absolute requirement e.g. brain

45
Q

Glycogen synthase regulation

A

Allosteric regulation in response to external conditions
GSa = active, b = inactive
Protein kinases e.g. PKA (starvation), AMPK (hypoxia), GSK3 (insulin-responsive,blocks PKA and AMPK), Ca-dependent (muscle in anaerobia), inactive to b
Protein phosphatase 1G activates, stimulated by G6P allosterically and through signalling pathways of insulin

46
Q

Glycogen phosphorylase

A

GPb = inactive, a = active

PP-1G inactivates, helped by G6P and insulin inactivate
Glycogen phosphorylase kinase phosphorylates b to activate it to GPa, AMP allosterically activates

(OPPOSITE TO SYNTHASE)

47
Q

Glycogen phosphorylase kinase regulation

A

GPKa and b again

GPKa - protein kinases activate by phosphorylating, stimulated by cAMP, Ca2+, AMP
=glycogen breakdown

GPKb - protein phosphatase 1G, stimulated by G6P and insulin

SAME AS SYNTHASE

48
Q

Glycogen compartmentation of regulation

A

Only one pair of enzymes activated at a time
Phosphorylase activity decreases rapidly with insulin
GS activation delayed until GP inactive

This is latency coordination - may be due to movement of phosphatases in the compartment

49
Q

CAC regulation

A

Many metabolic starting points i.e. glucose, FAs, ketones, AAs

Inputs have varying efficiencies e.g. some AAs better, favour FA

Controlled by citrate synthase, ATP and a-ketoglutarate dehydrogenase

Control also spares acCoA and AAs

50
Q

Carbohydrates to other metabolites?

A

Pentose phosphate pathway = nucleic acids

F16BP–PEP and acCoA from pyruvate = lipids

Oxaloacetate from pyruvate = AAs = proteins

51
Q

Isoenzymes in pathway?

A 
GLUT
Hexokinases
PFK 
GP glycogen phosphatase
GS glycogen synthase
PK pyruvate kinase
PC pyruvate carboxylase
PEPCK
52
Q

Where does insulin/glucagon regulate?

A 
GLUT
Hexokinases
GP and GS
G6P -- pentose sugars (dehydrogenases G6PDH/6PGDH)
PFK
PK, PC, PDH, PEPCK
53
Q

Where does transcription regulate?

A

Hexokinases
G6P – pentose sugars (dehydrogenases G6PDH/6PGDH)
PFK
PK, PC, PEPCK

54
Q

Where does SREBP-1c regulate?

A

Hexokinases
G6P – pentose sugars (dehydrogenases G6PDH/6PGDH)
PDH, PEPCK

55
Q

Where does phosphorylation by PKA regulate?

A

Hexokinases
GP, GS
PFK
PK, PC, PEPCK

56
Q

Where does allosteric regulation occur?

A

GP, GS
PFK, F16BPase
PK, PDH

57
Q

Where does compartmentation control regulate?

A

GLUT
Hexokinase, G6Pase
GS, GP

Cell Metabolism and Metabolic Control (8 decks)

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