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Gastro > biochem - carbohydrate metabolism > Flashcards

biochem - carbohydrate metabolism Flashcards

1
Q

functions of glycolysis (3)

A
  • generate ATP without need for O2
  • provide substrates for further oxidation and ATP generation
  • provide intermediates for biosynthesis and regulation (glucose-6-P can be converted to many important molecules)
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2
Q

location of glycolysis

A
  • present in all cells
  • glycolysis occur in cytoplasm

*cells that do not have mitochondria (eg RBC) rely solely on glycolysis for ATP

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3
Q

how is hexokinase activity regulated

A
  • product inhibition -> inhibited by high G-6-P concentration
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4
Q

how is the liver able to undergo glycolysis even with high glucose concentration

A
  • presence of specialized isoenzyme -> GLUCOKINASE -> continued activity in high glucose conditions (can continuously produce glycogen with glucose)
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5
Q

how much ATP is obtained from one glucose molecule

A
  • 4 generated but 2 consumed -> overall net gain of 2 ATP molecules
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6
Q

what are the requirements for glycolysis

A
  • 2 NAD+, 2Pi, 2ATP per molecule of glucose
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7
Q

when can there be a shortage of NAD+ or Pi

A

NAD+
- if NAD+ is not regenerated from NADH

Pi
- if Pi is trapped in sugar phosphate form that is not metabolised (eg aldolase deficiency) -> cannot break down F-1,6-P2

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8
Q

how is NAD+ regenerated under oxygen/ no oxygen

A
  • oxidative phosphorylation in mitochondria (aerobic)
  • lactic acid fermentation (anaerobic)
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9
Q

how is glycolysis regulated in localized tissues

A
  • allosteric control -> affect enzymatic activity
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10
Q

how is glycolysis regulated systemically

A
  • hormonal control -> can have effect on both enzymatic activity and local tissue allosteric control
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11
Q

which enzyme is involved in local allosteric regulation

A
  • hexokinase (HK)
  • PFK-1
  • PK
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12
Q

described allosteric changes in HIGH energy need

A
  • PFK-1 upregulated by F-2,6-P2 (formed from fructose-6-P when F6P accumulates, catalysed by PFK-2/FBP-2 complex) -> cause breakdown of F6P even faster
  • PFK-1 upregulated by high levels of AMP (product of ATP degradation, signals ATP depletion)
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13
Q

describe allosteric changes in LOW energy need

A
  • PFK-1 downregulated by ATP (builds up when muscle is relaxed)
  • PFK-1 downregulated by citrate
  • HK downregulated by G6P
  • PK downregulated by ATP
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14
Q

describe action of the PFK2/FBP2 enzyme

A
  • PFK2 portion of enzyme catalyses formation of F-2,6-P from F6P -> upregulate PFK-1
  • FBP2 portion of enzyme catalyses breakdown of F-2,6-P -> downregulate PFK-1
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15
Q

describe hormonal control of PFK-2 in liver

A
  • hormones (insulin/ glucagon/ epinephrine) regulate PFK-2/FBP-2 complex
  • controls level of F-2,6-P2 -> controls activity of PFK-1
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16
Q

describe the effects of glucagon/ epinephrine on PFK2/FBP2

A
  • phosphorylates PFK2 -> only FBP2 active -> breakdown F-2,6-P -> downregulate glycolysis
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17
Q

describe effect of insulin on PFK2/FBP2

A
  • opposite of glucagon & epinephrine
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18
Q

describe hormonal control of PK in liver

A
  • glucagon phosphorylate (inactivates) PK
  • insulin activates PK
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19
Q

when is glucagon/ epinephrine released by liver

A
  • low glucose levels -> conserve glucose by decreasing glycolysis
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20
Q

when is insulin released

A
  • high glucose levels -> increase breakdown of glucose to form other byproducts (eg glycogen) or energy
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21
Q

how does glycolysis byproducts produce 2,3-BPG & its effects

A
  • 1,3-BPG can be converted to 2,3-BPG via MUTASE
  • 2,3-BPG binds to HbO2 -> decreases affinity of Hb for O2 -> releases O2
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22
Q

genetic diseases in glycolysis of glucose

A
  • GENETIC -> pyruvate kinase (PK) deficiency
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23
Q

effects of PK deficiency

A

RBC
- glycolysis is IMPT for RBC energy -> PK deficiency cause RBC lysis (lack of energy)
- block in pathway cause more 2,3-BPG product formation in RBC

LIVER
- increase compensatory synthesis of PK in liver cells

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24
Q

diseases of fructose/ galactose glycolysis

A

FRUCTOSURIA
- fructokinase deficiency -> fructose accumulation excreted in urine (benign condition)

FRUCTOSE INTOLERANCE
- aldolase B deficiency -> accumulation of fructose-1-P + depletion of phosphate (required for glycolysis) -> poor feeding, unable to thrive

GALACTOSEMIA
- galactose-1-P uridyltransferase deficiency -> galactose-1-p build up (toxic)
- presentations: cataracts (galactose converted to galacticol and deposited in lens); liver enlargement, brain damage

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25
Q

functions of TCA cycle (3)

A
  • generate energy
  • provide intermediates for biosynthesis
  • provide feedback regulator (citrate) to other pathways
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26
Q

location of TCA

A
  • inside mitchondria
  • pyruvate -> converted to acetyl CoA -> sent into mitochondria
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27
Q

Regulation of PDH complex (2)

A
  • allosteric regulation
  • phosphorylation of PDH (by kinase & phosphatase)
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28
Q

how is PDH regulated under high energy need (eg exercising)

A

allosteric regulation
- increase CoASH and NAD+ -> allosteric activation of PDH
- muscle activity increase Ca2+ -> activate phosphatase -> dephosphorylate inactive, phosphorylated PDH to active PDH
- presence of ADP and pyruvate inhibits kinase -> prevents phosphorylation of PDH

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29
Q

how is PDH regulated under low energy need (resting)

A
  • NADH increase (not consumed by TCA) -> inhibit PDH
  • acetyl-CoA accumulates along with NADH (not used up by TCA cycle) -> activate kinase -> phosphorylate PDH
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30
Q

function of anaplerotic reactions

A
  • replenish oxaloacetate when it is depleted for biosynthesis
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31
Q

can ethanol replenish TCA cycle intermediates and increase metabolism?

A
  • NO. ethanol is converted to acetyl-CoA -> 2C compound, cannot replenish TCA cycle intermediates
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32
Q

how is TCA regulated at high energy demand (eg exercise)

A

Isocitrate dehydrogenase
- high ADP concentration -> activate isocitrate DH
- Ca2+ produced by muscles -> activate isocitrate

a-ketoglutarate dehydrogenase
- Ca2+ activate a-KG

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33
Q

how is TCA regulated at low energy demand

A

isocitrate dehydrogenase
- end product inhibition: NADH

malate dehydrogenase
- NADH levels rise -> end product inhibition

citrate synthase
- citrate levels rise -> end product inhibition

34
Q

genetic diseases of TCA cycle

A
  • pyruvate dehydrogenase deficiency
  • TCA enzymes deficiency
35
Q

PDH deficiency pathogenesis

A
  • pyruvate not metabolised to acetyl-coA -> converted to lactate -> ACIDOSIS (cause neurodegeneration)
  • poor muscle tone,
    developmental delay, seizures

*treat: anti-epileptics, diet (10% carbs)

36
Q

TCA enzymes deficiency (very rare) pathogenesis

A
  • fumarase/ succinate DH/ a-KG DH
  • similar presentations and pathogenesis as PDH deficiency (backflow of pyruvate)
37
Q

acquired disorders of TCA cycle

A
  • thiamine deficiency
  • arsenic/ mercury poisoning
38
Q

thiamine deficiency pathogenesis

A
  • thiamine required for pyruvate DH and a-KG DH function
  • thiamine deficiency -> decrease ATP production

presentations
- poor muscle control; neurodegeneracy; HF

39
Q

arsenic/ mercury poisoning pathogenesis

A
  • inhibit lipoic acid (required by PDH and a-KG DH complexes) -> decrease ATP production; neurodegeneracy; coma/death
40
Q

location of oxidative phosphorylation

A
  • mitchondrial membrane
41
Q

types of shuttles that transport NADH into mitochondria

A
  • glycerol-3-phosphate shuttle -> transports into mitochondria as FADH2, less biochemical steps but less energy efficient
  • malate-aspartate shuttle -> transports into mitochondria as NADH, more biochemical steps but more efficient (more commonly found in cardiac muscles/ tissues that need higher energy pdn efficiency)
42
Q

which complex in ETC cannot pump protons out of mitchondrial membrane

A

complex II

43
Q

overall ATP yield from oxidative phosphorylation

A

8NADH x 2.5 = 20
4FADH2 x 1.5 = 6

44
Q

side products of oxidative phosphorylation

A
  • partial reduction of O2 -> forms reactive oxygen species (toxic)
  • heat generated when H+ passes through UCP protein instead (UCP present in brown fat) of ATP synthase -> short circuit route
45
Q

how is oxidative phosphorylation regulated at high ATP needs

A
  • high ATP consumption -> increase [ADP] in mitochondria -> increase conversion at ATP synthase -> increase need for O2 at ETC
46
Q

how is oxidative phosphorylation regulated at low ATP needs

A
  • ATP not utilized -> decrease need for ATP at ATP synthase
47
Q

genetic diseases of OXPHOS

A
  • OXPHOS mitochondrial disease; depends on maternal inheritance and replicative segregation
48
Q

OXPHOS mitochondrial disease presentations

A
  • disruption in gene decrease ETC complex & ATP production
  • MELAS SYNDROME - Myopathy, Encephalomyopathy,
    Lactic Acidosis and Stroke)
49
Q

which complexes are coded by mitochondrial DNA?

A
  • complex I, III, IV
  • ATP synthase

*female with defect in complex II will LIKELY NOT pass on mutation to children (nuclear mutation, lower chance of passing on than mitochondrial mut)

50
Q

acquired diseases of mitochondrial DNA

A
  • mitochondrial poison
51
Q

types of mitochondrial poisons

A

complex I
- rat poison

complex III
- fish poison

complex IV
- cyanide, CO

proton leak across mt membrane (through UDP)
- herbicides/ pesticides

52
Q

functions of HMP shunt (2)

A
  • generate NADPH
  • generate ribulose-5-phosphate for nucleotide synthesis
53
Q

where does HMP shunt function

A
  • cytoplasm
54
Q

which cells are HMP shunt majorly found in

A
  • adipocytes (NADPH for fatty acid synthesis)
  • liver (NADPH for fatty acid syn & drug metabolism)
  • adrenal cortex (NADPH for steroid synthesis)
  • RBC (NADPH for glutathione reduction, helps to neutralise ROS)
  • WBC (NADPH for superoxide generation)
55
Q

what can be used as an assay to gauge thiamine levels

A
  • transketolase activity in RBCs (transketolase requires thiamine pyrophosphate prosthetic group to function)
56
Q

how is HMP shunt regulated

A
  • rate of G6PD enzyme is regulated -> based off NADPH/ NADP+ ratio
  • supply of NADPH low -> G6PD more active -> increase HMP shunt
57
Q

functions of NADPH (5)

A
  • reducing power for biosynthesis (eg cholesterol synthesis)
  • detoxification in liver
  • generating ROS in WBCs
  • generating NO for vasodilation
  • glutathione reduction
58
Q

congenital disease of HMP shunt

A
  • G6PD deficiency
59
Q

G6PD deficiency pathogenesis

A
  • X-linked recessive, range of clinical symptoms due to different mutations in G6PD gene
  • G6PD deficiency -> decreased production of NADPH in RBCs needed to maintain glutathione
  • glutathione reduces ROS -> ROS builds up (oxidative stress) causing oxidation of proteins -> reduce membrane plasticity -> hemolysis

presentations
- jaundice (excessive hemolysis), kernicterus, anemia

60
Q

contraindications in G6PD deficient patients

A
  • antimalarials
  • sulfur based antibiotics (eg cotrimoxazole)

*increases ROS in body -> cannot be removed by lack of reduced glutathione

61
Q

what is a benefit of having G6PD deficiency

A
  • resistance to malaria infections (NADPH is utilized by plasmodium in RBC to survive)
62
Q

function of gluconeogenesis

A
  • maintaining blood glucose levels during long fasts (glycogen used for short fasts)

*order of sources for maintaining glucose: diet carbs -> glycogen (4-24hr) -> gluconeogenesis (>24hr)

63
Q

location of gluconeogenic pathway

A
  • cytosolic (except pyruvate carboxylase in mitochondria; glucose-6-phosphatase in endoplasmic reticulum)

organs
- liver and kidney

64
Q

substrates for gluconeogenesis

A

LACTATE; ALANINE; other amino acids
- entry via pyruvate

GLUTAMINE, other amino acids
- entry via oxaloacetate

GLYCEROL (from lipolysis)
- entry via glycerol-3-P

65
Q

how is gluconeogenesis regulated at high energy needs

A

allosteric regulation
- ATP, citrate increase activity of F-1,6-BP
- acetyl CoA increase activity of pyruvate carboxylase

66
Q

how is gluconeogenesis regulated at low energy needs

A

allosteric regulation
- AMP inhibits F-1,6-BP
- ADP inhibits both PEPCK and PC

67
Q

how is gluconeogenesis regulated at high glucose levels

A

hormonal regulation
- increase insulin secretion -> increase F-2,6-P -> inhibits F-1,6-BP

68
Q

how is gluconeogenesis regulated at low glucose levels

A

hormonal regulation
- glucagon secretion -> decrease F-2,6-P -> decrease inhibition of F-1,6-BP
- glucagon secretion -> increase transcription of G-6-phosphatase, fructose-1,6-biphosphatase, PEP carboxykinase

69
Q

genetic diseases of gluconeogenesis

A
  • glucose-6-phosphatase deficiency
  • pyruvate carboxlase deficiency
70
Q

glucose-6-phosphate deficiency pathogenesis

A
  • glucose cannot be formed in the last step -> glucose-6-P diverted to glycogen formation (ORGANOMEGALY) and HMT shunt (nucleotide metabolism -> INCREASE URIC ACID)
  • backpressure on gluconeogenesis -> accumulation of pyruvate -> form lactate

presentations: organomegaly, hyperuricaemia, lactic acidosis

71
Q

pyruvate carboxylase deficiency pathogenesis

A
  • pyruvate accumulates (cannot be converted to oxaloacetate) -> reduced ATP pdn from TCA; increase acetyl-CoA via PDH catalysis; increase lactate buildup

*short life span (6months)

72
Q

acquired disease of gluconeogenesis

A
  • diabetes mellitus
  • relative/ absolute insulin deficiency -> unopposed glucagon action even in fed state -> stimulates gluconeogenesis
73
Q

can ethanol contribute to maintaining blood glucose levels if a person just drinks alcohol w/o carbohydrates/ protein

A
  • NO. ethanol is converted to acetyl-CoA, which enters TCA cycle for energy pdn -> DOES NOT contribute to gluconeogenesis
74
Q

where does glycogen formation/ metabolism occur

A
  • cytoplasm, present in most cell types

*glucose-6-phosphatase only present in liver (required for glucose export)

75
Q

how is glycogen metabolism regulated

A

tissue response:
- allosteric/ phosphorylation -> regulate glycogen breakdown/ synthesis

systemic response:
- hormonal -> directly cause glycogen breakdown/ synthesis + stimulate allostery/ phosphorylation in tissues

76
Q

regulation in liver in fed state (high glucose, ATP)

A

allosteric regulation
- increase amt of glucose-6-P activates glycogen synthase -> increase pdn of glycogen from UDP-glucose
- glucose-6-P, glucose & ATP inhibits glycogen phosphorylase (liver isoform) -> prevent breakdown of glycogen to glucose

77
Q

regulation in liver in fasted state (low glucose, ATP)

A

allosteric regulation
- low glucose, glc-6-P, ATP -> no more activation of glycogen synthase
- glycogen phosphorylase no longer inhibited -> glucose produced

78
Q

regulation in muscles at high energy needs (high AMP, Ca)

A

allosteric regulation
- AMP directly activates glycogen phosphorylase (muscle isoform)
- Ca -> binds to calmodulin -> activates kinase -> phosphorylate & activates glycogen phosphorylase

79
Q

regulation of muscles at low energy needs (high ATP, glc-6-P)

A
  • increase ATP, glc-6-P -> activates glycogen synthase -> increase conversion of UDP-glucose to glycogen
  • ATP, glc-6-P -> inhibit glycogen phosphorylase
80
Q

systemic regulation of glycogen metab at high glucose vs low glucose

A

HORMONES
high glucose
- insulin signalling -> insulin binds to RTK -> phosphorylate IRS (insulin receptor substrate) -> activate PP1 (protein phosphatase 1)
- PP1 dephosphorylate (ACTIVATES) glycogen synthase -> glycogen synthesis
- PP1 dephosphorylate (INACTIVATE) glycogen phosphorylase -> inhibit glycogen breakdown

low glucose
- glucagon & epinephrine signalling -> glucagon (liver) & epinephrine (liver/ muscle) binds to GPCR -> dissociation of heterotrimeric G protein -> a subunit activate adenylate cyclase -> ATP convert to cAMP -> activate PKA
- PKA phosphorylate (INACTIVATE) glycogen synthase
- PKA phosphorylate phosphorylase kinase -> phosphorylates (ACTIVATE) glycogen phosphorylase

Gastro (20 decks)

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