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KIN 217 - Human Biochemistry > Chapter 16 > Flashcards

Chapter 16 Flashcards

1
Q

Glucose

A
  • Glucose = principal carbohydrate of all living system
  • Sufficient supply of glucose in our system is important for brain and blood cells since glucose = main source of ATP in these cells
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2
Q

Glucose is a prominent fuel b/c…

A
  1. Glucose may have been available for primitive biochemical systems b/c it can form under prebiotic conditions
  2. Glucose is the most stable hexose (spends more time in cyclic form)
  3. Glucose has a low tendency to nonenzymatically glycosylate proteins
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3
Q

Explain how net yield of ATP works

A

Although four ATP molecules are produced in the second half, the net gain of glycolysis is only two ATP because two ATP molecules are used in the first half of glycolysis

  • 2 ATP (used) + 4 ATP (generated) = net yield of 2 ATP
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4
Q

Basics of Glycolysis

A

Process:
1. One glucose, 6-carbon molecule, gets converted into two pyruvate, 3-carbon molecules

  1. Glycolytic reactions utilize 2-ATP molecules but generate 4-ATP molecules for a net yield of 2-ATP

Further Notes:
- Glycolysis = energy conversion pathways

  • Location = cytoplasm
  • The bioconversion involves multiple steps (10-steps) and multiple enzymes
  • Enzymes are organized into large complexes which enhances enzyme and overall pathway efficiency
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5
Q

Stages of Glycolysis

A

Process:
- Stage 1: Glucose is trapped into cells by converting glucose into fructose 1,6-biphosphate through a series of steps that utilize 2-ATP molecules

 in these reactions, glucose is modified, phosphorylated, and rearranged to create two 3-carbon compounds that are phosphorylated

  • Stage 2: each of the two 3-carbon compounds are oxidized into pyruvate

 these reactions generate 2-moleules of ATP per 3-carbon compound, for total of 4-ATP and net ATP-yield of 2-ATP

Further Notes:
- Stage 1 = investment stage
- Stage 2 = yield stage

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6
Q

Glycolysis: Stage 1 – Reaction 1

A
  1. First reaction is catalyzed by enzyme hexokinase trapping glucose into cell by forming glucose-6-phosphate or G6P
  2. First reaction requires input of energy w/ cost of 1-ATP
  • ATP supplies 1 phosphoryl group that’s added to hydroxyl group of carbon 6 of glucose
  1. Activity of hexokinase requires divalent cation (magnesium Mg2+ or Mn2+). Mg2+ acts as cofactor to catalyze reaction
  2. Enzyme substrate-binding induced fit of glucose in cleft (hydrophobic, extrudes water) of globular hexokinase enzyme occurs to minimize hydrolysis of ATP

Further Notes:
- Glucose will fit snugly w/ enzyme’s hydroxyl group on carbon 6 exposed, which provides easy access for transfer of terminal phosphoryl group from ATP to hydroxyl group

  • Absence of water molecules is important. Presence of water molecules could lead to hydrolysis of ATP into ADP and Pi, and loss of Pi group
  • Substrate binding induced fit model favors glucose phosphorylation and minimizes ATP-hydrolysis
  • Reaction = IRREVERSIBLE & major regulatory step of glycolytic pathway
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7
Q

What is isomerization?

A

transformation of a molecule into a different isomer

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8
Q

Glycolysis: Stage 1 – Reaction 2

A

Process:
1. Glucose-6-phosphate is converted to fructose 6-phosphate (from G-6-P to F-6-P)

  1. This is an isomerization catalyzed by enzyme phosphoglucose isomerase (PGI)
  2. Aldose (glucose-6-phosphate) is converted into ketose (fructose 6-phosphtae)

Further Notes:
- Reaction is REVERSIBLE
- In open-chain form, G6P = aldose and F6P = ketose

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9
Q

Glycolysis: Stage 1 – Reaction 3

A

Process:
1. Fructose 6-phosphate is converted into fructose 1,6-biphosphate

  1. Reaction is catalyzed by enzyme phosphofructokinase (PFK)

Further Notes:
- Reaction is IRREVERSIBLE

  • Reaction is important regulatory step in pathway. This reaction is considered the commitment step for pathway
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10
Q

A bisphosphate is a compound with ______ phoshate groups

A

2

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11
Q

Glycolysis: Stage 1 – Reaction 4

A

Process:
1. Fructose 1,6-biphosphate is split into two 3-carbon molecules: dihydroxyacetone phosphate (DHAP: a ketone) and glyceraldehyde 3-phosphate (GAP: an aldehyde)

  1. Reaction is catalyzed by enzyme aldolase

Further Notes:
- Reaction is REVERSIBLE

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12
Q

Glycolysis: Stage 1 – Reaction 5

A

Process:
1. Dihydroxyacetone phosphate (DHAP) is converted into glyceraldehyde 3-phosphate (GAP) via enzyme triosephosphate isomerase (TPI)

Further Notes:
- This is a REVERSIBLE isomerase reaction

  • DHAP to GAP is required since DHAP cannot proceed along glycolysis, while GAP readily progresses through glycolysis
  • At equilibrium, 96% of the triose phosphate is in DHAP form, but this is readily converted into GAP since GAP moves through glycolysis allowing for a shift in equilibrium

We now have 2 glyceraldehyde-3-phosphate molecules, so stage 2 will happen TWICE

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13
Q

Triose phosphate isomerase enzyme deficiency

A

Triose phosphate isomerase enzyme deficiency is lethal (DHAP builds up, GAP not generated, glycolysis insufficient) and is characterized by severe hemolytic anemia and neurodegeneration

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14
Q

Glycolysis: Stage 2 – Reaction 1

A

Process:
1. Glyceraldehyde 3-phosphate is converted into 1,3-biphosphoglycerate (1, 3-BPG)

  1. Reaction is catalyzed by enzyme glyceraldehyde 3-phosphate dehydrogenase
  2. Reaction involves oxidation-reduction reaction and generates NADH
  • Glyceraldehyde 3-phosphate dehydrogenase oxidizes GAP w/ removal of hydride ion from GAP that’s transferred to NAD+. GAP = donor molecule. NAD+ = acceptor molecule. GAP is oxidized. NAD+ is reduce to NADH

Further Notes:
- 1, 3-BPG has high phosphoryl transfer potential, greater than ATP
- Reaction is REVERSIBLE

There are two steps in this reaction:

  1. There is an oxidation of an aldehyde, which thermodynamically favorable
  2. Reduction of NAD+ (unfavorable acyl phosphate formation)
  • NAD+ acts as a co-enzyme, which is required for enzymatic activity
  • The dehydration reaction (formation of the acyl phosphate) is thermodynamically unfavorable
  • Coupling reactions helps drive entire process
  • Reactions are coupled through formation of a thioester intermediate
  • The thioester intermediate reduces the extreme barrier and facilitates reaction and formation of end-product w/ acyl phosphate
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15
Q

Glycolysis: Stage 2 – Reaction 2

A

Process:
1. 1,3-biphosphoglycerate (1,3-BPG) is converted into 3-phosphoglycerate, which allows for the energy trapped in the oxidation of the carbon atom to be used to fuel ATP formation

  1. Reaction is catalyzed by enzyme phosphoglycerate kinase (PGK)
  2. ATP generated is via substrate level phosphorylation (substrate is 1,3-BPG, which is a kinase)

Further Notes:
- Reaction is REVERSIBLE

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16
Q

Glycolysis: Stage 2 – Reaction 3, 4, 5

A

Process:
1. 3-phosphoglycerate is converted into 2-phosphoglycerate via enzyme phosphoglycerate mutase

  1. The mutase will mediate an intramolecular shift of the phosphoryl group from C3 position to C2 position to generate 2-phosphoglycerate. Now, phosphate is closer to the carboxylate, which will facilitate the next step
  2. 2-phosphoglycerate is converted into phosphoenolpyruvate (PEP) via enzyme enolase

 this is a dehydrogenation reaction in which enzyme enolase introduces a double bond to create an enol phosphate w/ even greater phosphoryl transfer potential since phosphate group is trapped in an enol tautomer

  1. PEP = unstable molecule in which the phosphate prevents electron sharing. The unstable PEP is then converted into pyruvate via enzyme pyruvate kinase

 here, the phosphoryl group from PEP is transferred to ADP to generate ATP

Further Notes:
- The energy for overall conversion of 2-phosphoglycerate into pyruvate comes from an internal oxidation-reduction reactions: the C3 is more reduced, C2 is more oxidized

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17
Q

Net Reaction for Glycolysis

A
  • Net reaction for glycolysis starts w/ one molecule of glucose, plus 2-ATP, plus 2-NAD+ which, through a series of reactions, yield 2 molecules of pyruvate, 2-ATP, 2NADH, 2-H+, and 2-H2O
  • This net reaction will yield -90 kJ/mol (-22 kcal/mol) of energy
  • This is an aerobic reaction that takes place in cytoplasm of cells

glucose + 2 Pi + ADP + 2 NAD+ –> 2 pyruvate + 2 ATP + 2 NADH + (2 H+) + 2 H2O

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18
Q

NAD+ –> NADH + (H+)

A
  • NAD+ = necessary coenzyme for glycolysis
  • During pyruvate metabolism, NAD+ can be recovered from NADH. This can involve 3 possible fates for pyruvate:
  1. pyruvate oxidation into acetaldehyde than ethanol
  2. pyruvate into lactate
  3. pyruvate oxidation into acetyl-CoA, which will continue to undergo further oxidation
  • Niacin (vitamin-B3) is important component of NAD+
  • In absence of NAD+ regeneration (ex. if all the NAD+ is used and converted into NADH), glycolysis will be prevented
  • For glycolysis to proceed, NAD+ must be available
19
Q

Alcoholic fermentation

A
  • Conversion of glucose into two molecules of ethanol is called alcoholic fermentation
  • Fermentation reactions are means of oxidizing NADH
  • Fermentations are ATP generating pathways where electrons are removed from one organic compound and transferred to another
  • In ethanol production, formation of ethanol from pyruvate regenerates NAD+ in 2-steps
20
Q

Ethanol Production to Regenerate NAD+ in 2 steps

A

Step 1: pyruvate decarboxylate generates acetaldehyde

  • This enzyme requires the co-enzyme thiamine pyrophosphate, derived from thiamine (vitamin B1)
  • The CO2 that is generated would normally diffuse away, but instead contributes to the carbonation of alcoholic beverages

 In breadmaking w/ Bakers yeast, the CO2 generated allows bread to rise

Step 2: acetaldehyde then converted to ethanol via alcohol dehydrogenase

  • Here, NAD+ is restored and glycolysis can continue
21
Q

Series of reactions for maintaining redox balance in alcohol fermentation

A
  1. NADH is generated when glyceraldehyded-3-phosphate undergoes a dehydrogenation
  2. This NADH must be re-oxidized to NAD+ for glycolytic pathway to continue
  3. In alcohol fermentation, alcohol dehydrogenase oxidizes NADH and generates ethanol
22
Q

Lactic acid fermentation

A
  • NADH can also be oxidized by converting pyruvate into lactate in a reaction catalyzed by enzyme lactate dehydrogenase

 occur in humans under anaerobic conditions

Conversion of glucose into two molecules of lactate is called lactic acid fermentation

  • In this reaction, the electrons are transferred from NADH to substrate to regenerate NAD+
  • Obligate anaerobes cannot survive in presence of oxygen
  • Some obligate anaerobic microorganisms are pathogenic
  • Many food products (sour cream, yogurt, various cheeses, beer, wine, sauerkraut) result from fermentation
23
Q

Pathogenic Obligate Anaerobes

A
  • Fermentation reactions = main way energy is liberated
  • Obligate anaerobes listed below CANNOT survive in presence of oxygen
  1. Cloestridium tetani –> tetnus
  2. Cloestridium botulinum –> botulism
  3. Cloestridium perfringens –> gas gangrene
  4. Bartonella hensela –> cat scratch fever
  5. Bacterioides fragilis –> abdinoml, pelvic, pulmonary, and blood infections
24
Q

Glycolysis & Sugars

A
  • Along with glucose, other monosaccharides (namely fructose and galactose) can be channeled into the glycolytic pathway
  • Fructose is derived from table sugar or high fructose corn syrup (HFCS)
  • Galactose can be derived from milk sugar
  • Fructose & galactose can be converted into intermediates of glycolytic pathway

–> Galactose can be converted into G6P
–> Fructose can be converted into F6P

25
Q

Fructose

A
  • Fructose-6-phosphate = direct intermediate of glycolytic pathway
  • Many tissue cells (ex. adipose) can generate fructose-6-phosphate directly if cells have the enzyme hexokinase, but not all tissue cells can generate fructose-6-phospahte

 BUT NOT LIVER

Ex. in liver, fructose is converted (made) into fructose-1-phosphate by enzyme fructokinase

  1. Fructose-1-phosphate is split into dihydroxyacetone phosphate (DHAP) and glyceraldehyde via enzyme fructose-1-phosphate aldolase
  2. Dihydroxyacetone phosphate (DHAP) = another direct intermediate of glycolytic pathway
  3. Glyceraldehyde however must be converted to glyceraldehyde-3-phosphate (G3P) via enzyme triose kinase
26
Q

Excessive Fructose Consumption

A
  • Has been linked to obesity, fatty liver, and development of type 2 diabetes

–> This is b/c of the way fructose is taken up and processed in liver

  • Hepatocytes have a tendency for high uptake of fructose
  • In the liver, key regulatory enzyme of glycolysis, phosphofructokinase, is bypassed
  • High amounts of fructose can lead to unregulated synthesis of acetyl CoA. Excess amounts of acetyl CoA can lead to fatty acid production. Production of glyceraldehyde can lead to production of glycerol, which can lead to excessive triacylglycerol synthesis
27
Q

Galactose

A

Process:
–> Galactose is converted into glucose 6-phosphate by the galactose-glucose interconversion pathway. Pathway involves 4-steps:

  1. Phosphorylation converts galactose into galactose 1-phosphate via galactokinase
  2. A uridyl group is then added, which generates UDP-galactose and glucose 1-phosphate via enzyme galactose 1-phosphate uridyl transferase

–> Galactose 1-phosphate + UDP-glucose = UDP-galactose and glucose 1-phosphate

  1. Epimerization: UDP-galactose is epimerized to UDP-glucose via enzyme UDP-galactose-4-epimerase
  2. The glucose 1-phosphate is isomerized into glucose 6-phosphate via phosphoglucomutase

–> Glucose 6-phosphate = direct intermediary of the glycolytic pathway

28
Q

Lactose Intolerance

A
  • People unable to digest lactose experience lactose intolerance
  • Intolerance = when adults lack enzyme lactase to degrade lactose (low levels of enzyme lactase), thus, lactose isn’t digested or absorbed
  • In lactase deficient individuals, gut bacteria metabolize lactose generating methane (CH4) and gas (H2) which disrupts the water balance in intestine

–> This can result in flatulence, abdominal pain, discomfort, and diarrhea

  • Northern Europeans have a mutation that prevents the decline of lactase activity after weaning. This mutation was beneficial b/c of availability of milk from dairy farming
29
Q

Regulating Glycolysis (General overview)

A
  • Glycolytic pathway = tightly controlled
  • Enzymes that catalyze the irreversible reactions in metabolic pathways = very important regulatory and control sites
  • 3 irreversible enzymes of glycolysis:
  1. Hexokinase
  2. Phosphofructokinase (PFK)
  3. Pyruvate kinase
  • Regulation = tissue dependent
  • In muscle cells for glycolysis, regulatory needs will be met by ATP
  • In liver cells, regulation is met by the diverse roles of liver

–> Role of liver in blood glucose maintenance is important for regulation of glycolysis in liver

  • Reversible reactions will follow flow dictated and controlled by irreversible reactions
30
Q

Regulating Glycolysis: PFK (muscle)

A
  • PFK = key regulator of glycolysis in mammals
  • PFK = allosterically inhibited by ATP and stimulated by AMP
  • High level of ATP inhibits PFK by decreasing affinity for F6P, while AMP diminishes the inhibitory effect of ATP
  • Presence of AMP stimulates the activity instead of ADP b/c enzyme adenylate kinase can form ATP from ADP
  • Since ATP can be generated from ADP, we’re able to salvage some ADP, thus AMP becomes signal for low energy state
31
Q

Regulating Glycolysis: Hexokinase (muscle)

A
  • Hexokinase = allosterically inhibited through feedback inhibition by its product glucose-6-phospahate
  • Build-up of glucose-6-phosphate indicates that cell no longer needs glucose. Glucose will remain in blood
  • A rise in glucose-6-phosphate concentration is a means why which PFK communicates w/ hexokinase

–> when PFK is inactive, concentration of F6P rises, thus levels of G6P also increase, b/c it is an equilibrium

  • Inhibition of PFK leads to inhibition hexokinase
  • PFK = main regulatory enzyme and commitment step for glycolysis since G6P is also a substrate for glycogen synthesis
  • Conversion of F6P to fructose 1,6-biphosphate = irreversible reactions that is unique to glycolytic pathway
32
Q

Regulating Glycolysis: Pyruvate Kinase (muscle)

A
  • Pyruvate kinase = regulatory enzymes that catalyzes reaction from phosphoenolpyruvate to pyruvate
  • Pyruvate = central intermediate that can be used to generate ATP or used as a precursor for biosynthetic pathways
  • When there’s excess ATP, ATP will allosterically inhibit the enzyme pyruvate kinase to decrease rate of glycolysis, and ATP synthesis, since high levels of ATP = cells energy needs are being met
  • If there’s excess pyruvate: alanine synthesized from pyruvate by adding an amine

–> reactions occurs when high pyruvate levels
–> alanine inhibits pyruvate kinase

  • If there’s excess fructose 1,6-biphosphate, which indicates a buildup of an upstream precursor, this will stimulate the enzyme pyruvate kinase to keep up
  • Pyruvate kinase is inhibited by the allosteric signals ATP and alanine and stimulated by fructose 1,6-biphosphate, the product of PFK reaction
33
Q

Regulation of Glycolysis: (muscle)

A
  • At rest glycolysis is not very active
  • High concentration of ATP inhibits PFK and pyruvate kinase
  • G6P is converted into glycogen
  • During exercise, the decrease in ATP/AMP ratio resulting from muscle contraction activates PFK (hence glycolysis)
  • The flux down the pathway is increased
34
Q

Liver Glycolysis – PFK

A
  • For regulation of glycolysis in liver, PFK = key regulator
  • PFK is regulated by citrate, which will inhibit PFK activity
  • Fructose 2,6-biphosphate stimulates PFK activity

–> F-2,6-BP will be in excess when there are high amounts of F6P

  • ATP = important regulator in liver cells, but NOT as critical as a regulator compared to muscle cells (more critical)
35
Q

Liver Glycolysis – Glucokinase

A
  • Hexokinase = allosteric enzyme in liver as it is for muscle cells
  • Glucokinase (hexokinase IV) = primarily responsible for phosphorylating glucose in liver
  • Glucokinase = isoenzyme of hexokinase
  • Glucokinase = active ONLY after a meal when blood glucose levels are high
  • Glucokinase = lower affinity for glucose then hexokinase (higher Km). This lower affinity allows glucose to be utilized by other tissues (ex. brain, muscle)

–> Uptake only when blood glucose concentrations are high

  • Glucokinase = not inhibited by G6P

–> this allows glucokinase to continue to trap glucose in liver when there is high concentration of glucose

  • High blood glucose (glucose taken up by liver) can be utilized for glycogen storage or fatty acid synthesis
36
Q

Liver Glycolysis – Pyruvate Kinase

A
  • Pyruvate kinase = allosterically regulated in liver, same as in muscle
  • Inhibitors: alanine and ATP
  • Activators: fructose 1,6-biphosphate
  • Liver pyruvate kinase = regulated by covalent modification via phosphorylation
  • Phosphorylation shuts enzyme off, which is triggered by glucagon signaling in response to low blood glucose
  • This mechanism spares blood glucose for tissues rather than uptake into liver
37
Q

Glucose Transporters

A
  • Glycolysis = influenced by family of transporters that enable glucose to enter and leave mammalian cells
  • GLUT 1 and GLUT 3 have low Km (high affinity)

–> These transporters mainly supply erythrocytes (GLUT 1) and the brain (GLUT3) w/ steady flow of glucose

  • GLUT 2 has high Km (low affinity)

–> accommodates for the post-prandial glucose response

  • GLUT 4 has a moderate Km value and is insulin dependent

** GLUT 1 & 3 are in mammalian tissue
** GLUT 2 is in liver and pancreatic B cells (regulates insulin. in liver, removes excess glucose from blood)
** GLUT 4 is in muscle and fat cells
** GLUT 5 is in small intestine

38
Q

Glucose Sensing & Insulin Release

A

Process:
- Glucose uptake in pancreas is linked to insulin secretion

  1. Insulin is secreted by beta cells of the pancreas in response to high blood glucose levels
  2. Secretion is stimulated by metabolism of glucose in beta cells
  3. Glucose enters beta cells through GLUT2 and is metabolized to pyruvate
  4. Pyruvate is oxidized to CO2 and H2O
  5. Increase in ATP closes potassium channels, which alters the charge across the cell membrane
  6. This opens calcium channels. Influx of calcium ions stimulates release of insulin
39
Q

Galactosemia

A
  • The disruption of galactose metabolism
  • The most common form, classic galactosemia, is an inherited deficiency in galactose 1-phosphate uridyl transferase activity
  • Afflicted infants fail to thrive. They vomit or have diarrhea after consuming milk
  • Enlargement of liver and jaundice are common, sometimes progressing to cirrhosis
  • Cataracts will form, and lethargy and retarded mental development are common
  • blood-galactose level is markedly elevated, and galactose is found in urine. Absence of transferase in RBC is definitive diagnostic criterion
40
Q

Treatment of Galactosemia

A
  • Most common treatment is to remove galactose (and lactose) from diet
  • Although elimination of galactose from diet prevents liver disease and cataract development, most patients still suffer from central nervous system malfunction, most commonly delayed acquisition of language skills. Female patients also display ovarian failure
41
Q

Warburg effect

A
  • For decades, tumors have been known to display enhanced rates of glucose uptake and glycolysis
  • Warburg effect = rapidly growing tumor cells that metabolize glucose to lactate even in presence of oxygen (also called called aerobic glycolysis)
  • Although originally observed in cancer cells, warburg effect is also seen in noncancerous, rapidly dividing cells
42
Q

Gross
Guys
Favor
Fat
Butts
Good
Boys
Prefer
Pretty Girls In
Pink
PJ’s

A

Glucose
Glucose 6-phosphate
Fructose 6-phosphate
Fructose 1,6-bisphosphate
Glyceraldehyde 3-phosphate
1,3-bisphophglycerate
3 phosphoglycerate
2 phosphoglycerate
Phophoenolpyruvate
Pyruvate

43
Q

Helen
Paints
Pictures
Along the
Training
Ground
Praying
People
Enjoy
Painting

A

Hexokinase
Phosphogluco isomerase
PFK
Aldolase
Triphohsphate isomerase
Glyeraldehyde 3-phosphate dehydrogenase
Phosphoglycerate kinase
Phosphoglycerate mutate
Enolase
Pyruvate kinase

KIN 217 - Human Biochemistry (34 decks)

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