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Medical Biochemistry > Metabolism > Flashcards

Metabolism Flashcards

ATP, TCA, Glycolysis, Oxidative Phosphorylation, Fatty acid synthesis

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USMLE® Step 1 flashcards
1
Q

cellular location of cholesterol synthesis

A

cytosol with some enzymes bound to membrane of ER

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2
Q

the function cytosolic glycerophosphate dehydrogenase

A

used with glycerophosphate shuttle Accepts 2 e from NADH and transfer them to dihydroxyacetone phosphate DHAP (Cytosol) DHAP converts back to glycerol-3-phosphate FADH2 is produced (matrix)

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3
Q

The impact of decreased activity of G6Pase on Pyruvate and glucose

A

red. G –> hypoglycemia
inc. pyr –> lactic acidosis

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4
Q

Addition of a two-carbon unit to an acetyl group on fatty acid synthase:

  • ACP
  • FA synthase
  • Condensation B-ketoacyl formation
A
  • First, an acetyl moiety is transferred from acetyl CoA to the Acyl-Carrier Protein (ACP)
  • The malonyl group attaches to the phosphopantetheinyl residue of the ACP of the FA synthase
  • The acetyl group condenses with the malonyl group
  • CO2 is released and
  • a 3-ketoacyl group is formed
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5
Q

Enolase inhibitor

(inhibition of substate level phosphorylation)

A

Fluoride inhibits enolase resulting in a decrease in ATP synthesis

Note: Blood samples for glucose quantification are collected in tubes containing fluoride.

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6
Q

The enzyme that catalyzes the last TCA rxn

A

malate dehydrogenase

malate + NAD+ → OAA + NADH + H+

»Oxaloacetate is also produced by:

˃Transamination of Asp

˃Carboxylation of pyruvate

»Oxaloacetate is recycled in TCA cycle

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7
Q

The conformational change of this ATPsynthase allows the synthesis of ATP

A

passing of the protons through F0 channel in the ATP Synthase Complex

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8
Q

Status of [HMG-CoA Reductase_p]

A

inactive (promoted by glycogen)

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9
Q

The effect of glucagon on the short-term regulation of HMG-CoA Reductase

A

Insulin activates phosphatase Phosphatase dephosphorylate the [HMG-CoA Reductase_p] and makes it active [HMG-CoA Reductase_X] is active

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10
Q

the effect of insulin on hormone sensitive lipase

A

inhibition

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11
Q

The effect of acetyl CoA concentration on pyruvate carboxylase

A

When Acetyl Co-A is high –> pyruvate carboxylase is activated

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12
Q

the effect of low cholesterol on transcription of HMG-CoA reductase

A

1- SCAP-SREP translocation from ER to Golgi (movement) 2- Cleaved by S1P and S2P proteases (liberation) 3- SREP translocates to the nucleus and activates transcription. movement, liberation, translocation, activation

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13
Q

List the mitochondrial dehydrogenases that donate electrons to Co-Q

A

From ETC- Both complex I and II ( I is NADH dehydrogenase and II is succinate dehydrogenase) Glycerophosphate dehydrogenase (glycerophosphate shuttle) Acetyl CoA dehydrogenase

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14
Q

A mitochondrial disorder, leads to lactic acidemia, developmental delay, seizure, extraocular palsies, hypotonia and ultimately death by the age of 2 years

A

Leigh disease

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15
Q

The major cause of congenital lactic acedemia

A

Pyruvate dehydrogenase deficiency

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16
Q

The malfunctioning of these two ATP transporters of mitochondrial leads to necrotic cell death

A

ANT and VDAC

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17
Q

major sites of de novo cholesterol synthesis

A

Most tissues are capable of cholesterol formation but the major de novo synthesis takes place in: liver intestine adrenal cortex and reproductive tissues

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18
Q

Patients with this disorder suffer from early progressive liver failure and neurologic abnormalities, hypoglycemia and increased lactate in the body fluids. The also have reduced levels of ETC complexes ( I, II, II, IV) due to reduction in synthesis.

A

Fatal Infantile Mitochondrial Myopathy

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19
Q

Gluconeogenesis key reactions

A
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20
Q

Lactate dehydrogenase deficiency

A

Deficiency of lactate dehydrogenase leads to muscle cramping and myoglobinuria after intense exercise (LDH M isoform childhood-onset)

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21
Q

Increased [F-2,6-BP] causes:

A

Inhibition of gluconeogenesis

Activation of:

Glycogenesis

Glycolysis, and

Lipogenesis

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22
Q

the rxn catalyzed by G3PDH

and the inhibitor of G3PDH

A

Phosphorylation of GAP using Pi*

•Glyceraldehyde 3-phosphate dehydrogenase (G3PDH), with NAD+ as a cofactor, catalyzes the phosphorylation of GAP yielding:

•1,3-BPG, and

•NADH*

Arsenate inhibits glyceraldehyde 3-P dehydrogenase (competes with Pi for the active site)

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23
Q

amino acid degradation as anaplerotic rxns of TCA

A

»Degradation of amino acids

˃Oxaloacetate from Asp

˃a-ketoglutarate from Glu

˃Succinyl CoA from

+Val and Ile in all tissues except liver

+ Met, Thr, and odd-chain FAs

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24
Q

Pyruvate kinase deficiency

A

Deficiency in pyruvate kinase, an autosomal recessive trait, causes a decrease in ATP production leading to the disturbance in the cell membrane gradient and loss of ions and water causing the RBCs to contract, crenulate, and die (nonspherocytic hemolytic anemia- dead RBC). The resulting accumulation of 2,3-diphosphoglycerate (2,3-DPG) shifts the Hb-O2 dissociation curve to the right.

Inc. 2,3-DPG

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25
Q

The status of glycerophosphate shuttle when the cytosolic NADH/NAD is lower than in mitochondria

A

Active regardless

Active even when the cytosolic NADH/NAD+ is low

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26
Q

un form of lipoprotein from the liver

A

VLDL

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27
Q

3 ways to produce oxaloacetate

A
  1. TCA-malate dehydrogenase (last step: malate –> OAA)
  2. ASP transamination
  3. Pyruvate carboxylation
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28
Q

inhibits glucokinase

A

F6P

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29
Q

The enzymes necessary for gluconeogenesis from glycerol

(glycerol is a minor source)

A
  1. Hormone sensitive lipase- makes glycerol
  2. Glycerol kinase- makes glycerol 3 phosphate
  3. Gycerol 3P dehydrogenase- makes DHAP from G3P
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30
Q

The effect of increased [F2,6-bisP] on glycolysis (in muscle)

A
  • In the muscle, PFK-2 is:
  • Activated by↑[AMP] and ↑[norepinephrine] resulting in increased [F2,6-bisP] → activation of glycolysis → ATP synthesis for muscle contraction.
  • The allosteric effecter F-2,6-BP is synthesized in a reaction catalysized by phosphofructokinase-2 (PFK-2):

F6P → F2,6-bisP

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31
Q

Relative affinity of HbF and HbA to 2,3-BPG

A

HbF has a lower affinity for 2,3-BPG than does HbA. Consequently HbF has a higher affinity for O2, which facilitates the unloading of O2 at the maternal-fetal interface

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32
Q

Elongation of fa synthesis

A
  • Activated palmitate can be elongated two carbons at a time in the ER
  • Malonyl CoA donates the two-carbon units
  • NADPH provides the reducing power
  • The major elongation is

Palmitoyl-CoA (C16) → Stearyl-CoA (C18)

•Very long-chain FAs (C22 → C24) occur especially in the brain

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33
Q

Gluconeogenesis importance

Source of glucose between meals

A

Between meals, glucose is released via glycogenolysis

nWhen the liver stores are depleted, gluconeogenesis is essential for survival during:

Sleep

Long term fasting, or

Starvation

Gluconeogenesis is the synthesis of glucose de novo

using noncarbohydrate sources

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34
Q

The active and inactive forms of HMG-CoA reductase

A

[HMG-CoA Reductase_p] active (Glucagon and amp-activated PKK) [HMG-CoA Reductase_X] inactive (Insulin and phosphatase)

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35
Q

•Fatty Acid Synthase (FAS)

A
  • Cytoplasmic multifunctional enzyme
  • The growing chain of FA is attached to Acyl-Carrier Protein (ACP) of FAS
  • The addition of each two-carbon unit is followed by two reduction reactions using NADPH
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36
Q

both NADPH and NADH require this vitamin

A

Niacin

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37
Q

fa desaturation

linoleic desaturation

A
  • The produced fatty acids will be used to synthesize several compounds such as:
  • components of complex lipids of biological membranes
  • Desaturation occurs in the ER and requires:
  • Molecular oxygen (O2)
  • NADH
  • Cytochrome b5
  • Dietary linoleic acid is

desaturated at carbon 5 to produce arachidonyl-CoA

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38
Q

Inactive PDC is

A

Phosphorylated (by PDC kinase)

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39
Q

The effect of glucagon on the short-term regulation of HMG-CoA Reductase

A

Glucagon ( and AMP-Activated PKK) phosphorylate and activate [AMP-Activated PK_p] then Phosphorylates the HMG-CoA reductase and makes it inactive [HMG-CoA Reductase_p]

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40
Q

•Deficiency of this complex leads to mitochondrial encephalopathy, lactic acidosis, and stroke (MELAS) disorder

A

•Deficiency in NADH:Ubiquinone oxidoreductase (complex I) leads to mitochondrial encephalopathy, lactic acidosis, and stroke (MELAS) disorder

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41
Q

Allosteric effect of F-2,6-BP on F-1,6-BPase

A

F-2,6-BP allosterically inhibits F-1,6-BPase

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42
Q

Pyruvate Dehydrogenas complex

a- Components

b- required coenzymes

c- deficiency of coenzymes

A

»A multisubunit complex with three enzymatic activities

»Requires five coenzymes for its activity:

˃Thiamine pyrophosphate, lipoic acid, CoA, FAD and NAD+

»Deficiencies in thiamine (B1) or niacin (B3) can cause neurological and cardiovascular disorders due to:

˃An inability to generate ATP

˃Accumulation of TCA cycle precursors (lactic acidosis)

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43
Q
  1. The enzymes by which the liver overcomes the irreversible reactions of glycolysis (during gluconeogenesis)
  2. Which ones are missing in muscles?
A

The liver overcomes the irreversible reactions using:

A. Pyruvate carboxylase (PC) (absent in muscles)

B. Phosphoenolpyruvate carboxykinase (PEPCK)

C. Fructose-1,6-bisphosphatase (F-1,6-BPase)

D. G-6-Phosphatase (absent in muscles)

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44
Q

Fate of cytosolic citrate (fa synthesis)

A

citrate lyase (aka citrate cleavage enzyme) breaks citrate down into:

Acetyl co A and OAA

Later, OAA–>malate –> pyruvate

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45
Q

The TCA step that forms fumarate

enzyme and its location

A

»Succinate dehydrogenase converts succinate to fumarate

succinate + E-FAD → fumarate + E-FADH2

˃embedded in the inner mitochondrial membrane as part of Complex II

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46
Q

Specificity and function of VDACs

A

Votlg-Dep Anion Channel (outer mt membrane) Nonspecific and allow different molecule to cross membrane: Phosphate, chloride, pyruvate, citrate, ADP and ATP Several kinases such as hexokinase bind to cytosolic part of these channels to have access to newly synthesized ATP

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47
Q

The enzymes required for fatty acid synthesis

A

Acetyl-CoA carboxylase

Fatty acid synthase (FAS)

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48
Q

the effect of increase in I/g ratio on acetyl Co-A synthesis

A
  1. dephosphorylation of PDC (insulin activates PDC phosphatase)
  2. increased in synthesis of:
    1. malic
    2. G6Pdehydrogenase
    3. citrate lyase
  3. citrate accumulation –> inhibited isocitrate dehydrogenase –> citrate leaving mitochondria

All caused by and increase in insuling

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49
Q

4 general parameters for TCA regulation

A
  1. citrate ynthase (depends on the reactants and products)
  2. liver NADH/NAD+ ratio impact on acetyl-coA
  3. NADH/NAD+ ration effect on dehydrogenases
  4. Ca2+ enhances the the production of NADH (first 2)
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50
Q

results in decreased levels of glucose in CSF (cerebrospinal fluid), which leads to intractable seizures in infancy and developmental delay

A

GLUT-1 deficiency syndrome hereditary disease affecting the NS.

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51
Q

% of dietary cholesterol absorbed from diet

A

50%

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52
Q

Complex II: components and function ETC-OXPhos

A

Succinate dehydrogenase electrons from the succinate dehydrogenase– catalyzed oxidation of succinate to fumarate move from the coenzyme, FADH2 to an Fe-S protein

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53
Q

The short term regulation of glucagon and insulin on HMG-CoA reductase activity

A

Insulin functions via phosphatase- forms the active form [HMG-CoA Reductase_X] Glucagon and active AMP-Acivated Protein Kinase-P(PK-P)- Promote the inactive form [HMG-CoA Reductase_p]

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54
Q

dephosphorylated HMG-CoA reductase is

A

active

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55
Q

•Phosphoglucose isomerase (GPI)

Phosphoglucose isomerase deficiency

A

Conversion of G6P to F6P

•The isomerisation of G-6-P into F-6-P is catalyzed by Phosphoglucose isomerase (GPI)

Phosphoglucose isomerase deficiency leads to hydrops fetalis, a severe form of the deficiency. Most severe cases do not survive to birth.

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56
Q

fa synthesis summary

A
  • FAs synthesis is catalyzed by acetyl-CoA carboxylase and fatty acid synthase
  • Both enzymes are tightly regulated
  • FAs are the components of complex lipids
  • Essential FAs must be provided by diet
  • Some of the essential FAs can be transformed by elongation and desaturation to allow for the synthesis of other molecules such as:
  • Prostaglandins and other eicosanoids
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57
Q

the products form during NADH oxidization by malate dehydrogenase (cytosolic isoenzyme)

A

malate dehydrogenase is a shuttle for NADH (sine innter mitochondrial membrane dosnt have a transporter for NADH). Oxaloacetate reduction to malate

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58
Q

NADH shuttles of mitochondria (Cytosol–> matrix)

A

glycerophosphate shuttle glycerophosphate dehydrogenase malate-aspartate shuttle malate dehydrogenase

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59
Q

chylomicrons

A

transport of biliary and dietary cholesterol from intestine

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60
Q

Hexokinase a- reaction b- inhibition c- function

A

a- catalyzes the phosphorylation of Glucose. G6P is the finial product. b- Inhibited by G6P c- traps the glucose inside the cell

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61
Q

The irreversible rxns of glycolysis:

A

Phosphorylation rxns e.g. G –> G6P F6P –> F1,6-bisP

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62
Q

What gets transported into the matrix via malate-asp shuttle:

A

malate moves into the matrix

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63
Q

These diseases are caused by:

  1. Defeciency in NADH:Ubiquinone oxidoreductase
  2. point mutation (mtDNA) for genes that code for:
    • NADH:Ubiquinone oxidoreductase OR
    • NAHD dehydrogenase
A

1- MELAS

2- LHON

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64
Q

reaction catalyzed by cytosolic malate dehydrogenase

A

OAA to malate while using NADH

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65
Q

Biotinidase deficiency

A

Biotinidase deficiency, an autosomal recessive trait, is a disorder in which the body is unable to reuse and recycle biotin. It is classified as a multiple carboxylase eficiency.

Signs and symptoms appear within the first months of life but the age of onset varies. Profound deficiency leads to seizures, weak muscle tone (hypotonia) breathing problems and delayed development. If not treated with biotin supplement, the disorder leads to hearing loss, vision loss, hair loss (alopecia), ataxia, skin rashes, and candidiasis.

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66
Q

The effects of F1P on fructokinase

A

inhibition

but prior to inhibiton of fructokinase, F1P causes ATP overuse (aka AMP overload)

As AMP conc. inc., more AMP will be degraded, if excessive –> uric acid formation

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67
Q

Justify hypoglycemia in fructose intolerance

A

Reactions catalyzed by aldolase:

1- eavage of fructose 1,6-bisphosphate (central reaction to glycolysis), and

2- condensation gyceraldehyde phosphate, and dihydroxyacetone phosphate to form fructose 1,6-bisphosphate

•F1,6 BP is essential for gluconeogenesis

•Absence of F1,6 BP leads to low glucose de novo synthesis

•Justifies hypoglycemia in fructose intolerant patients

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68
Q

The action of GSIS is mediated by this molecule found on B- cells of the pancreas:

A

Glucokinase (generally found in liver and pancreas) in B-cells it functions as glucose sensor to regulate GSIS (Glucose Stimulated Insulin Secretion).

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69
Q

GLUT-1

A

Glucose transporter of the brain ( Glial cells express this transporter) and erythrocytes (RBCs)

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70
Q

Rate limitting Step of TCA

A

The oxidation and decarboxylation of isocitrate catalyzed by isocitrate dehydrogenase

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71
Q

The Smith-Lemli-Opitz Syndrome (SLOS) is an autosomal recessive human malformation syndrome resulting from an inborn error of cholesterol synthesis.

A

3β-hydroxysterol ∆7-reductase

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72
Q

What gets transported into the matrix via glycerophosphate shuttle

A

Glycerol-3-phosphate

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73
Q

insulin-dependent glucose transporter of adipose and muscle tissues

A

GLUT-4

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74
Q

Hexokinase vs Glucokinase 1- location 2- Vmax

A

Hexokinase is found in most tissues ( low Vmax and low Km) But Glucokinase is unique to liver and pancreas (high Vmax and Km)

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75
Q

Regulation of Gluconeogenesis through the regulation of Fructose 1,6 bisphosphatase

A

nInsulin and glucagon regulate gluconeogenesis

nF-1,6-BPase is allosterically regulated

nF-2,6-BP allosterically inhibits F-1,6-BPase

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76
Q

Regulation of gluconeogenesis in liver and muscle

A

High levels of glucagon activate lipolysis

In the liver, the increase [acetyl CoA]:

Stimulates gluconeogenesis

Inhibits PDH

Allosterically activates pyruvate carboxylase

In the muscle, glucose utilization is limited by:

Low GLUT-4, &inhibition of PDH by high [acetyl CoA]

Lipolysis in muscle Leads to:

increased [acetyl CoA], which causes

§the inhibition of PDHC, leading to

§the conversion of pyruvate to lactate → liver via Cori cycle for use in gluconeogenesis

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77
Q

Aldolase Deficiency and Fructose intolerance

A

It catalyzes the cleavage fructose-1 phosphate into D-glyceraldehyde and dihydroxytacetone phosphate

•D-glyceraldehyde is then phosphorylated into glyceraldehyde-3-phosphate (GAP)

•GAP is an intermediate in glycolysis and gluconeogenesis

  • If F1P is not cleaved → accumulation → inhibition of fructokinase → accumulation of fructose in the blood.
  • Before inhibition of fructokinase, formation of F1P → ATP overuse and accumulation of AMP
  • Degradation of AMP → uric acid formation
  • If lactate is high → reabsorption of uric → uricemia
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78
Q

Compounds that regulate the HMG-CoA reductase in short-term by promoting proteolytic cleavage of the enzyme

A

@ H. conc. Cholesterol @ H. conc. bile The bind to HMG-CoA reductase and make it more susceptible to proteolytic cleavage

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79
Q

The mt. location in which the electron and H+ electrolchemical has its highest conc.

A

across the inner mitochondrial membrane

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80
Q

The role of acetyl-CoA and NADH on PDC regulation

A

Acetyl-CoA and NADH (products of PDC) activate PDC kinase ([PDC-P] is inactive).

Activated PDC kinase causes inhibition of PDC

Acetyl-Coa and NADH are also negative allosteric regulators of PDC

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81
Q

Regulation of pyruvate kinase (liver)

A

activated by F1,6-BP

inhibited by phosphorylation (glucagon, epinephrine, PKA and inc. cAMP)

Inhibited bu ATP, Alanine

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82
Q

Phosphorylated PK (pyruvate kinase) and PDC are

A

inactive

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83
Q

The molecule that accepts electron from NADH dehydrogenase and succinate dehydrogenase

A

Coenzyme Q

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84
Q

Phosphorylated HMG-CoA reductase is

A

inactive

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85
Q

Regulation of acetyl Co-A synthesis

A
  • Cytosolic acetyl-CoA generation is stimulated by the increase in insulin/glucagon ratio
  • Insulin activates pyruvate dehydrogenase
  • Pyruvate dehydrogenase is activated by dephosphorylation
  • Insulin activates the PDC phosphatase
  • Insulin also induces the synthesis of:
  • Malic enzyme
  • Glucose-6-phosphate dehydrogenase, and
  • Citrate lyase
  • The accumulation of citrate is due to the inhibition of isocitrate dehydrogenase
  • This accumulation leads to citrate leaving the mitochondria
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86
Q

Factor determining the fate of pytuvate in acetyl-coA production

A

pyruvate can get converted to acetyl coA by pyruvate dehydrogenase.

Pyruvate also can get converted to OAA by pyruvate carboxylase.

When Acetyl Co-A is high –> pyruvate carboxylase is activated

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87
Q

The component of ETC without an proton pump

A

Complex II- succinate dehydrogenase (since it dosnt span the membrane

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88
Q

The main form of glucose storage mainly found in liver and muscle

A

Glycogen

89
Q

Glucogenic a.a. used in gluconeogenesis

The enzymes

A
  1. Alanine
    1. Alanine aminotransferase (ALT)
    2. Ala –> pyruvate
  2. Aspartate
    1. Aspartate aminotrasferase (AST)
    2. Asp —>OAA–>PEP
      1. OAA–>PEP catalyzed by PEPcaroboxykinase
      2. Asp+malate –> oxaloacetate (malate shuttle)
  3. Glutamate
    1. Glutamate dehydrogenase (DLDH)
    2. Glu –> a-ketoglutrrate (a-ketoglutrate –> OAA –> PEP
90
Q

Rate limitting enzyme (rxn) of FA synthesis

reaction

required coenzymes

A

•Cytosolic Acetyl-CoA is converted to malonyl-CoA by an addition of a carboxyl group

•Biotin and ATP are required for this reaction

•*Acetyl CoA carboxylase is the rate-limiting enzyme of FA synthesis

91
Q

List the components of ETC

A

I- FMN, FAD-containing dehydrogenases CoQ Cytochrome bc1 Cytochrome c Cytochrome oxidase a+a3

92
Q

MODY type 2 cause: manifestation: treatment:

A

mutation in the pancreatic glucokinase gene (autosomal dominant disorder) manifest as nonprogressive hyperglycemia can be managed by diet alone

93
Q

1st step of cholesterol biosynthesis

A

begins with two condensation reactions 3-acetyl-CoA –> HMG-CoA

94
Q

The coenzymes of a-ketoglutrate dehydrogenase and the impact of chronic alcohol consumption

A

Coenzymes: thiamine pyrophosphate, lipoic acid, FAD, NAD+, and CoA*

chronic consumption of alcohol leads to vitamin B1/thiamine, deficiency that is normally converted to thiamine pyrophosphate for use as a coenzyme. Symptoms of this deficiency are neurological due to insufficient energy generation within the nervous system.

95
Q

Rate limitting, irriversible reaction and comitted step of glycolysis

A

Conversion of F6P to F-1,6- BP

•The phosphorylation of F6P is catalyzed by phosphofructokinase-1 (PFK-1) yielding F-1,6-BP (rate limiting and irreversible reaction; committed step)

Phosphofructokinase deficiency causes an inefficient use of glucose stores by RBCs and muscle leading to hemolytic anemia and muscle cramping.

96
Q

The function of medications that inhibit HMG-CoA reductase

A

statins- cholesterol lowering drugs

97
Q

The role of EPINEPHRINE in uncoupling of ETC and thermogenesis

A

act hormone-sensitive lipase –> relase of FAs free FA activation of thermogenin CoQ reduction of ATP synthesis

98
Q

Low [ADP] and ETC functioning

A

inhibits the ETC when ADP is low

99
Q

Regulation of Acetyl Co-A carboxylase

A
  • Acetyl CoA carboxylase is regulated by:
    1. Phosphorylation
  • Inhibited by AMP-activated protein kinase
  • Activated by dephosphorylation
    1. Allosteric modification:
  • Activated by citrate
  • Inhibited by palmitoyl-CoA
    1. Induction of its synthesis
  • High insulin/glucagon ratio induces its synthesis
100
Q

The enzyme and the rxn of the glycolysis that yields the first ATP

A

Formation of ATP through Substrate-level phosphorylation

  • A Phosphoglycerate kinase catalyzed reaction yields:
  • The first ATP, and
  • 3-phosphoglycerate (substrate for 2,3-Bisphosphoglycerate synthesis)
101
Q

respiratory control of energy production

A

Low ADP or P –> low ATP

Low ADP –> blocks NADH and FADH2 oxidation

Accumulation of NADH and FADH2 –> depletion of the oxidized form

102
Q

Name an inhibiter of complex V of ETC

What is the end result of ETC inhibition

A

Oligomycin bind to ATP-synthase (complex V) and blocks H+ channels

ETC and phosphorylation are tightly coupled, inhibition PHOS inhibits OX as well.

103
Q

3 biologically active compounds that utilize cholesterol as a precursor

A

bile acids/salts steroid hormones (pregnenolone) vit. D

104
Q

Two inhibitors of substrate level phosphorylation

A

Floride and arsenate

105
Q

The effects of Oligomycin on ETC, as well asthe blood and urine lactate levels.

A

Oligomycin inhibits ATP-synthase and blocks H+ channel

Results in high levels of accumulation of lactate in blood and urine

106
Q

Decreased [F-2,6-BP] causes:

A

qInhibition of glycolysis

qActivation of gluconeogenesis, and

qActivation of lipolysis

107
Q

Reduction of a β-ketoacyl group on the fatty acid synthase complex .

NADPH is the reducing agent

A
  • The ketone group is reduced to an alcohol
  • Dehydration occurs by removing water
  • The double bond is reduced
  • NADPH provides the reducing power
108
Q

The big pics of the usage of glucogenic aa. in gluconeogenesis

A

To make either PYR,OAA

Pyruvate made from alanine (ALT)

OAA made directly from aspartate (AST)

OAA made indirectly from glutamate (GLDH makes a-ketoglutrate and aketoglutarate is converted to OAA)

109
Q

Location and the purpose of hydroxyl group in cholesterol

A

C3 of the ring required for esterification (compared to sterol, cholesterol has OH and a side chain at C17 and a double bond C5 and C6

110
Q

Induce of expression of various cytochrome mono-oxidase

A

Drug and alcohol

Drug and alcohol abusers prone to deleterious effects of ROS formed by P-450s

111
Q

Regulation of the enzyme that catalyzes the aldol condensation step of TCA

A

»First step of TCA is the formation of citrate

oxaloacetate (OAA) + acetyl CoA + H2O → citrate + HS-CoA + H+

˃citrate synthase catalyzes aldol condensation

»Citrate synthase is inhibited by

˃Citrate (product inhibitor)

˃NADH

˃Succinyl CoA

»Regulation is determined by availability of substrates

112
Q

Patient with this mt. disorder develop l_oss of central vision in their 20s to30s._

A

Leber’s hereditary optic neuropathy

Complx I disorder- caused by point mutation (mtDNA) for genes that code for:

NADH:Ubiquinone oxidoreductase OR

NAHD dehydrogenase

113
Q

The sources of acetyl CoA for the biosynthesis of cholesterol are:

A

B-oxidation of fatty acids Dehydrogenation of pyruvate Oxidation of Ketogenic amino acids.

114
Q

The corticosteroids made from pregnenolone are:

A

glucocorticoids and mineralocorticoids Both are referred to as corticosteroids

115
Q

thermogenin

A

UCP of the brown adipose tissue associated with heat production Non-shivering thermogenesis

116
Q

function and location of HMG-CoA reductase

A

ER membrane bound enzyme required for the committed step of cholesterol biosynthesis

117
Q

The effects of(liver) the increase [acetyl CoA]:

(gluconeogenesis)

A

Stimulates gluconeogenesis

Inhibits PDH

Allosterically activates pyruvate carboxylase

118
Q

Aldolase deficiency and fructose intolerance

Rxns catalyzed by alsolase B

A
  1. cleavage fructose-1 phosphate into D-glyceraldehyde and dihydroxytacetone phosphate
  2. cleavage of fructose 1,6-bisphosphate (central reaction to glycolysis),
  3. condensation of glyceraldehyde phosphate, and dihydroxyacetone phosphate to form fructose 1,6-bisphosphate
119
Q

»When energy levels in the cell are high

˃ATP depresses TCA cycle activity and leads to accumulation of citrate and its efflux to cytosol

A

»Cytosolic citrate stimulates

˃FA synthesis (Acetyl-CoA carboxylase)

»Cytosolic citrate inhibits

˃Glycolysis phosphofructokinase-1(PFK-1)

120
Q

The major source of C for TCA

A

Glycolysis

121
Q

Kearn-Sayre syndrome

A

caused by pt mutation of mt.DNA that impacts complex II

Patients with this syndrome present with short stature, complete external ophthalmoplegia, pigmentary retinopathy, ataxia and cardiac conduction defects

122
Q

reaction catalyzed by HMG-CoA reductase

A

HMG CoA + 2NADPH –> Mevalonate + 2NADP+

123
Q

Neuron-specific glucose transporter of the brain

A

GLUT-3 (NSGT)

124
Q

The ETC component capable of interacting with oxygen

A

cytochrome a+a3 (cytochrome oxidase)

125
Q

Three glycolytic enzymes that their transcription is controlled via Insulin/glucagon

A
  1. Glucokinase
  2. PFK-1
  3. Pyruvate kinase
126
Q

The reaction catalyzed by isocitrate dehydrogenase

A

»The oxidation and decarboxylation of isocitrate is catalyzed by isocitrate dehydrogenase (rate limiting step)

isocitrate + NAD+ → a-ketoglutarate + NADH + H+ + CO2

˃Allosterically

+activated by ADP and Ca2+

+inhibited by ATP and NADH

127
Q

Isocitrate formation

Inhibition of the rxn

A

»Citrate → isocitrate catalyzed by aconitase

˃Can be inhibited by fluorocitrate produced by citrate synthase from fluoroacetate (used as rodenticide and for wild life control)

+fluoroacetate is a potent toxin

+2-fluorocitrate → inhibits aconitase activity→ inhibits TCA cycle → death

128
Q

Regulation of the rate of oxygen consumption (ETC)

A

[ADP] HIGH: oxygen consumption is high, more NADHs are reduced and NAD+ returned to TCA. More H2O made

129
Q

Complex I: components and function ETC

A

NADH dehydrogenase (formation of NADH ) has Flavin Mono Nucleotide (FMN) At this complex electrons move from NADH to FMN to the Fe and Iron-Sulfur center and then CoQ

130
Q

Clinical Correlates summary of glycolysis and ATP generation

A

ØRed blood cells (RBCs) rely completely on glycolysis as a source of energy. Deficiencies of glycolytic enzymes will effect RBC function leading to hemolysis

ØHereditary deficiency of GLUT-1 results in decreased glucose in the cerebrospinal fluid, which leads to intractable seizures in infancy and developmental delay

ØDeficiency in the A isoform of aldolase (muscle and RBCs) leads to a nonspherocytic hemolytic anemia with episodes of rhabdomyolysis followed by a febrile illness

ØDeficiency of triose phosphate isomerase (TPI) leads to neonatal-onset hemolytic anemia, progressive hypotonia leading to eventual diaphragm paralysis and cardiomyopathy

ØEnolase is inhibited by fluoride. If patient’s blood sample for glucose quantification is collected in tubes containing fluoride

ØHbF has a lower affinity for BPG than does HbA, which leads to higher affinity for O2

ØMaturity-onset diabetes of the young (MODY) type 2, an autosomal dominant disorder, is caused by a mutation in the glucokinase gene leading to nonprogressive hyperglycemia, which can be managed by diet alone.

ØPhosphofructokinase deficiency causes an inefficient use of glucose stores by RBCs and muscle leading to hemolytic anemia and muscle cramping

ØDeficiency in pyruvate kinase causes a decrease in ATP production from glycolysis by RBCs leading to hemolytic anemia

131
Q

Regulation of TCA cycle

A

»Citrate synthase is

˃Regulated by availability of the substrate – oxaloacetate

˃Inhibited by its product, citrate and succinyl-CoA

»In the liver, NADH/ NAD+ ratio determines the fate of acetyl-CoA

˃High ratio – acetyl-CoA goes into ketone body synthesis

˃Low ratio – acetyl-CoA enters TCA cycle

»TCA cycle responds rapidly to

˃Changes in ATP/ADP and NADH/ NAD+ ratios

˃Increased ATP demand

»NADH/ NAD+ ratio regulates the activity of TCA dehydrogenases

˃High ratio leads to inhibition

˃Low ratio leads to activation

»Ca2+ activates the production of the first two NADH

132
Q

In form of lipoprotein from extrahepatic tissues

A

HDL

133
Q

Between hexokinase and glucokinase, which one has higher affinity to glucose:

A

hexokinase (thus it is reasonable that it is active in fasting state).

134
Q

Determine the targets of the following respiratory poisons:

1- Antimycin A

2- CO and CN-

A

1- Antimycin A (fungacide) inhibits Complex III

2- CO and CN- inhibits Complex IV

135
Q

activates glucokinase

A

glucokinase is activated by its substrate

136
Q

Palmitate Synthesis

A

Palmitate synthesis on the fatty acid synthase

Palmitoyl-CoA can be further elongated and desaturated to produce other fatty acids

137
Q

Anaplerotic reactions of TCA

general overview

A

low OAA –> inc. accumulation of acetyl-CoA –> activation of pytuvate carboxylase –> increased synthesis of OAA

138
Q

The effect of high acetyl coa on yruvate carboxylase

A

activation

(pyruvate carboxylase makes OAA from PYR in liver)

139
Q

GLUT-4 can be found in:

A

GLUT-4 is insulin-dependent glucose transporter of: 1- adipose tissue 2- muscle cells

140
Q

PFK2 activation in muscle and liver

A
  • In the liver, PFK-2 is:
  • activated by ↑[F6P] (the substrate), and
  • Inhibited by PKA during fasting conditions
  • Protein kinase A is activated by cAMP, the synthesis of which is induced by the binding of glucagon
  • In the muscle, PFK-2 is:
  • •Activated by↑[AMP] and ↑[norepinephrine] resulting in increased [F2,6-bisP] → activation of glycolysis → ATP synthesis for muscle contraction
141
Q

reation catalyzed bu malic enzyme

A

malate to pyruvate and making NADPH and CO2

142
Q

transporters of the inner mitochondrial membrane

A

Adenine Nucleotide Translocase (ANT) Phosphate transporters

143
Q

The effect of low cholesterol on transcription of HMG-CoA reductase

A

SCAP-SREBP remains intact, thus no gene activation

144
Q

Fate of cytosolic OAA during fa synthesis

A
  • OAA resulting from the cleavage of citrate is reduced to malate by cytosolic malate dehydrogenase (NAD+-dependent) in presence of NADH
  • Malate is then converted to pyruvate
  • In this reaction NADPH is produced and CO2 is released
  • The decarboxylation reaction is catalyzed by malic enzyme or NADP+-dependent malate dehydrogenase
  • NADPH will be used for reduction on the fatty acid synthase complex
145
Q

Determine the targets of the followoing respiratory poisons:

Amytal and Rotenone

A

Complex I of ETC

146
Q

The tissue most affected by arsenic poisioning

A

brain

Arsenic intereferes with glycolysis and TCA

147
Q

Acetyl-CoA carboxylase

A
  • Catalyzes the synthesis of malonyl-CoA
  • Malonyl-CoA is the immediate donor of the two-carbon units
148
Q

The lipoprotein(s) that don’t contribute to fasting plasma cholestrol

A

chylomicron- only found after a meal

149
Q

5 general pathways in which glucose is utilized:

A

Glycolysis Glycogen synthesis UDP-Glucose Pentose-Phosphate Pathway Sorbitol

150
Q

Sources of lactate

Lactate as a substrate (liver) of gluconeogenesis

A
  1. RBC
  2. Skeletal muscle
  3. skin
  4. lens and cornea

Lactate is the end product of glycolysis in the absence of oxygen:

RBCs

Intensely exercising muscle

151
Q

The disease that’s caused by pt mutation of mt.DNA that impacts complex II. Patients with this syndrome present with short stature, complete external ophthalmoplegia, pigmentary retinopathy, ataxia and cardiac conduction defects

A

Kearn-Sayre syndrome

152
Q

The impact of F2,6-bP reduction on glycolysis, gluconeogenesis, and lipolysis

A

reduction of F2,6-bp red. Glycolysis inc. gluconeogenesis inc. lipolysis

153
Q

Glucose enters brain via

A

GLUT-1 and GLUT-3

154
Q

Biosynthesis of mevalonate

A

Begins with HMG Co-A as the reactant second step of cholesterol biosynthesis, which is also the committed step and catalyzed by HMG-CoA reductase

155
Q

Aldolase B deficiency

A

•Deficiency of Aldolase B leads to pyruvate accumulation → lactate accumulation → lactic acidemia

156
Q

The enzymes responsible for the synthesis of:

  1. 2-Phosphoglycerate
  2. PEP
A

Synthesis of 2-phosphoglycerate

•Phosphoglycerate mutase moves phosphate to C-2 leading to the formation of 2-phosphoglycerate

Synthesis of phosphoenolpyruvate (PEP)

  • Enolase catalyzes a reaction leading to the formation of:
  • PEP, and
  • H2O
157
Q

The function of VDAC as a transporter in mt

A

diffusion of synthesized ATP out of the mt into the cytosol Voltage dependent anion channel

158
Q

Gluconeogenesis from Lactate

A

Lactate is the end product of glycolysis in the absence of oxygen:

  • RBCs
  • Intensely exercising muscle

The muscle lacks G-6-Pase and pyruvate carboxylase (PC) → cannot perform gluconeogenesis

Lactate from exercising muscle and RBCs → blood → liver → pyruvate → glucose (via gluconeogenesis) → blood → brain and RBCs (Known as Cori Cycle)

The reaction catalyzed by LDH is irreversible (lactate <–> pyruvate)

159
Q

Aldolase A deficiency and the rxn catalyzed by it

A
  1. Cleavage of F-1,6-BP
  • Aldolase catalyzes the cleavage of F-1,6-BP into:
  • Dihydroxytacetone phosphate (DHAP), and
  • Glyceraldehyde 3-phosphate (GAP)
  • Deficiency in aldolase A (muscle and RBCs) leads to a nonspherocytic hemolytic anemia with episodes of rhabdomyolysis (breakdown of muscle tissue) followed by febrile illness (kidney damage)
160
Q

list the cargos of adenine nucleotide antiporter in mitochondria Also list the direction of transport

A

1 ATP from matrix to cytosol 1 ADP from cytosol to matrix

161
Q

Sources of Acetyl CoA

A

Ethanol

Pyruvate (from glycolysis and aa, spc alanine)

The sugar (Glucose) (which makes pyruvate)

The ketone body-acetoacetate

The fatty acid- Palmitate

162
Q

liver F-1,6BPase deficiency

A

Deficiency of the liver F-1,6BPase leads to neonatal hypoglycemia, acidosis,irritability, tachycardia, dyspnea, hypotonia, and moderate hepatomegaly

163
Q

Cofactor for biotin carboxylase

A

biotin

164
Q

The enzyme that catalyzes the substrate level phosphorylation of TCA

A

»Succinate thiokinase catalyzes substrate-level phosphorylation

Succinyl CoA + Pi + GDP → succinate + GTP + CoA

»GTP and ATP are interconvertible:

GTP + ADP ↔ GDP + ATP

˃This conversion is catalyzed by nucleoside diphosphate kinase

165
Q

The events leading to the formation of an electrical and a PH gradient across the inner mitochondrial membrane

A

NADH and FADH2 donate electrons to ETC Leads to e- flow coupled with H+ transport

166
Q

The enzyme responsible for the conversion of DHAP to GAP and its deficiency

A
  1. Isomerisation of DHAP into GAP
  • Triose-P isomerase converts DHAP into GAP
  • Deficiency of triose phosphate isomerase (TPI) leads to neonatal-onset hemolytic anemia, progressive hypotonia leading to eventual diaphragm paralysis and cardiomyopathy
167
Q

Sources of NADPH for fa synth

A
168
Q

Hormonal effect on an allosteric Effector in the Regulation of Gluconeogenesis

  1. Insulin and Glucagon
  2. concentration of F-2,6-BP
A

In the presence of glucagon, F-2,6-BPase catalyzes

F-2,6-BP → F-6-P ( enters gluconeogenesis).

In the presence of insulin, PFK-2 catalyzes

F-6-P → F-2,6-BP

In short:

glucagon lowers F26BP, promote gluconeogenesis

Insulin increase F26BP, inhibits gluconeogenesis

169
Q

Components of the complex that regulates transcription of HMG-CoA reductase gene

A

SREBP (binds to SRE) SCAP-SREP cleavage activating protein

170
Q

The reaction catalyzed by a-ketoglutarate dehydrogenase

A

»The oxidative decarboxylation of a-ketoglutarate is catalyzed by a-ketoglutarate dehydrogenase complex

a-ketoglutarate + NAD+ + CoA è succinyl CoA + CO2 + NADH

˃Releases CO2 and produces the second NADH

˃Coenzymes: thiamine pyrophosphate, lipoic acid, FAD, NAD+, and CoA*

˃Inhibited by

+NADH and succinyl CoA (feedback inhibition) and

+ATP and GTP

˃Activated by

+Ca2+

171
Q

Formation of Gluconeogenic Intermediates From Carbon Sources

(main substrates for de novo synthesis in liver)

A

nTo synthesize glucose de novo, the liver uses as main substrates:

  • Glucogenic amino acids (from the muscle)
  • Lactate (product of anaerobic glycolysis )
  • Glycerol (Triglyceride catabolism/lipolysis)

nGlycogen in the muscle is NOT used to maintain blood glucose

172
Q

Purpose of Cori Cylce

A

Allows gluconeogenesis from lactate.

Since muscles lack PC and G6Pase, the lactate produced enters the circulation and enters the liver.

In the liver, it gets converted to pyruvate (LDH), and to glucose (via gluconeogenesis)

173
Q

Pyruvate Dehydrogenase deficiencies

Causes and Symptoms

Mode of inheritance

Severity

A

»Pyruvate dehydrogenase deficiency is the major cause of congenital lactic acidemia.

»Symptoms are similar to pyruvate carboxylase deficiency

˃Leigh disease

»The most common PDC genetic defects are in genes coding for alpha unit of E1

˃The E1 alpha gene is X-linked but affects both males and females

+Categorized as X-linked dominant disorder

»The severe form of PDC deficiency presents with excessive lactic acidosis at birth

˃Accumulated pyruvate leads to lactic acid synthesis via LD

˃Results in neurological symptoms because the brain:

+relies on glucose as a main source for Acetyl CoA for energy and

+is highly sensitive to acidosis

174
Q

chylomicron remnants

A

In peripheral tissue chylomicrons are converted to chylomicron remnants

175
Q

Pyruvate Dehydrogenase

As a major source of acetyl-CoA

A

»A bridge between glycolysis and TCA cycle

˃Is not part of TCA cycle

»Converts pyruvate to acetyl-CoA

˃Key irreversible step

˃A major source of acetyl CoA

»Important site for regulation

176
Q

PDC

a- inhibition

b- activation

c- allosteric regulation

A

»PDC is inhibited by phosphorylation catalyzed by PDC kinase which is

˃PDC kinase activated by:

+ATP (high energy signal)

+Acetyl-CoA and NADH (Products of PDC)

˃PDC kinase inhibited by:

+ADP (low energy signal)

+Pyruvate (Substrate of PDC)

»PDC is activated by dephosphorylation catalyzed by PDC phosphatase which is

˃PDC phosphatase activated by:

+Calcium (Ca+)

»Allosteric Regulation of PDC:

˃Acetyl-CoA and NADH are negative allosteric effectors

˃CoASH and NAD+ are positive allosteric effectors

177
Q

The effect of insulin in citrate lyase

A

induction

Citrate lyase breaks down citrate into OAA and acetyl CoA

178
Q

Efflux of TCA intermediates

A

»High carbohydrate meal generates

˃Citrate efflux into cytosol for fatty acid synthesis

»During fasting malate is transported to cytosol and used in gluconeogenesis

»TCA provides carbon skeletons for amino acid synthesis

»In the brain, a-ketoglutarate is converted to neurotransmitters GABA and glutamate

»In the liver and bone marrow , succinyl CoA can be used to form heme*

179
Q

activation of transcription of HMG-CoA reductase gene is initiated by

A

SREBP binds to SRE (sterol regulatory complex.

180
Q

failure in the function of G6Pase

GSDI

A

failure in the function of glucose 6Pase results in accumulation of G6P leading to hepatomegaly, severe hypoglycemia causing lethargy, seizures, brain damage, increased bleeding, and growth retardation (GSD I name?)

181
Q

Glucose enters hepatic cells via

A

GLUT-2

182
Q

the state in which the following enzymes are active in (fed vs fasting state) a- Hexokinase b- glucokinase

A

a- hexokinase is active in fasting state- It has low km and vmax, ang higher affinity to glucose- also found in most tissues) b- glucokinase is active in fed state.

183
Q

Tissues that express GLUT 2

A

liver Kidney B cells (Pancreatic cells)

184
Q

The starting point for the biosynthesis of cholesterol

A

acetyl Co-A

185
Q

Citrate effects on fatty acid synthesis and glycolysis

A

Citrate

Is the source of acetyl carbon for fatty acid synthesis

Inhibits phosphofructokinase – glycolysis

Activates acetyl CoA carboxylase – fatty acid synthesis

186
Q

Glucokinase vs. Hexokinase (Km comparison)

A

Hexokinase has LOW km Glucokinase has HIGH Km Hexokinase, phosphorylates glucose to forms G6P.

187
Q

Products of PDC

A

Acetyl Co-A and NADH

188
Q

Regulatory subunits of PDC

A

PDC kinase (ihibitor) and PDC phosphatase(activator)

are regulatory subunit within PDC

189
Q

The Cause of ME-LA-S disorders

ME mitochondria encephalopathy

LA lactic acidosis

S stroke

A

Deficiency in complex I

NADH:Ubiquinone oxidoreductase

190
Q

GLUT-5 can be found in

A

small intestine and testes (Glut-5 is fructose specific)

191
Q

Conversion of glucose to cytosolic acetyl-CoA

A
  • In the cytoplasm and through glycolysis, glucose is converted to pyruvate
  • Pyruvate then enters the mitochondria to form:
  • acetyl coenzyme A (acetyl-CoA) (pyruvate dehydrogenase ) and
  • Oxaloacetate (pyruvate carboxylase)
  • Acetyl-CoA and OAA condense to form citrate
  • Citrate is transported to the cytosol (when in excess)
  • In the cytosol, citrate is cleaved into acetyl-CoA and OAA by citrate lyase
  • The action of citrate lyase requires ATP
  • Citrate lyase is induced by insulin
  • The fate of pyruvate is dictated by the levels of acetyl-CoA in the mitochondria
  • When [acetyl-CoA] is high:
  • Pyruvate carboxylase is activated
192
Q

synthesized ATP utilizes the transporter to translocate from the matrix into the inner membrane space

A

ANT adenine nucleotide translocase

193
Q

Mechanisms of arsenic poisioning

affected pathways

effects of arsenate and arsenite

the over effect on total [ATP]

the most affected organ

A

»Arsenic interferes with glycolysis and TCA cycle

˃Arsenate acts as phosphate analog and inhibits substrate-level phosphorylation reactions

˃Arsenite inhibits enzymes using lipoic acid as a cofactor

˃Both lead to decreased production of ATP --> Low [ATP]

»Affects the brain, causing neurological problems and eventually death

194
Q

The mutation of this gene cause MODY-type II MODY-maturity Onset Diabetes of the Young

A

mutation in pancreatic glucokinase

195
Q

Mechanism of action of bile salt sequestrant

A

A bile acid sequestrant will lower cholesterol by binding to bile acid and disrupting the circulation back into the liver. It will cause more bile acid to be excreted, and thus increasing the use of cholesterol through bile acid synthesis.

196
Q

Transporter with specificity for fructose transport

A

GLUT-5

197
Q

In addition to the high ADP, in cardiac mitochondrial, ——— activates the TCA, provides an additional push to ETC by increasing NADH production.

A

Ca

198
Q

Two possible ways to generate NAD+ from NADH

A
  1. In presence of oxygen:
  • Pyruvate is degraded to CO2 and H2O, and NADH
  • The reducing power of NADH enters the electron transport chain to generate ATP

Glycerol 3P and malate-aspartate shuttles

  1. In absence of oxygen:
    * Lactate dehydrogenase (LDH/LD) reduces pyruvate to lactate

Pyruvate + NADH ↔ Lactate + NAD+

This reaction is reversible and pH dependent

199
Q

Major anaplerotic enzyme and its deficiency

A

Pytuvate carboxylase

˃Is the major anaplerotic enzyme

˃Forms oxaloacetate from pyruvate

˃Is activated by acetyl CoA

˃Its deficiency can lead to lactic acidosis

200
Q

what activates Malate-Asp shuttle

A

Active only when

(NADH/NAD+) cytosolic > (NADH/NAD+) mitochondria

When more NADH in cytosol

201
Q

The lipoprotein(s) that contribute to fasting plasma cholesterol

A

LDL, VLDL, HDL

202
Q

glucokinase can be found in these tissues:

A

liver and pancreas (In the pancreas, it functions as glucose sensor in B-cells, where it controls glucose-stimulated insulin secretion (GSIS).

203
Q

How does the liver circumvent the irreversible reactions of glycolysis

A

nDuring gluconeogenesis, the liver has to circumvent the irreversible reactions of glycolysis

q1. Hexokinase (reversed by D)
q2. PFK-1 (reversed by C)
q3. Pyruvate kinase (reversed by A and B)

nThe liver overcomes the irreversible reactions using:

qA. Pyruvate carboxylase (PC)

qB. Phosphoenolpyruvate carboxykinase (PEPCK)

qC. Fructose-1,6-bisphosphatase (F-1,6-BPase)

qD. G-6-Phosphatase

204
Q

Short-Term Regulation of HMG-CoA reductase

Phos/ Dephos

A

Inhibited by phosphorylation

Low ATP (through AMP-activated protein kinase) and Glucagon promote phosphorylation

Activated by dephosphorylation

Insulin activates phosphatase

205
Q

Transcriptional Regulation of HMG-CoA reductase

A

High cholesterol prevents its cleavage:

No activation of HMG-CoA reductase expression.

When cholesterol level is low:

SCAP-SREBP complex translocates from ER to Golgi and is cleaved by S1P and S2P proteases.

Liberated SREBP’s DNA-binding domain translocates to nucleus and activates transcription of many genes including HMG-CoA reductase gene.

206
Q

Synthesizes cholesterol esters

A

ACAT

Acey-CoA Cholestrol Acyltransferase

207
Q

Smith-Lemli-Opitz Syndrome (SLOS)

A

•The Smith-Lemli-Opitz Syndrome (SLOS) is the example of a human malformation syndrome resulting from an inborn error of cholesterol synthesis.

–Autosomal recessive

–Caused by the deficiency of 3β-hydroxysterol ∆7-reductase

•Infants with severe variant ( type II SLOS) often die from multiple congenital abnormalities.

208
Q

deficiency 3β-hydroxysterol ∆7-reductase

A

SLOS

209
Q

Cholestrol excretion

A

Sterol ring cannot be degraded by humans.

It is excreted either as biliary cholesterol or in form of bile acids.

Most of the excreted bile acids are reabsorbed in the gut through an enterohepatic circulation.

210
Q

Components of bile

Bile acid sequestrants function

A

Bile acid sequestrants are used to lower cholesterol through a decreased bile acids reabsorption in the gut.

Bile contains bile acids, cholesterol, lipids, and bilirubin.

211
Q

The rate limitting step of bile acid biosynthesis is catalyzed by:

The function of bule acids

A

Rate-limiting step is catalyzed by 7a-hydroxylase:

The enzyme is inhibited by the bile acids (end-product inhibition).

They facilitate the absorption of fat-soluble vitamins and drugs.

Prevent precipitation of cholesterol in the gallbladder.

212
Q

Bile Salts

A

Bile salts are produced by conjugation of bile acids with glycine or taurine.

They have lower pK than bile acids and are better detergents.

They can be converted to secondary bile salts by intestinal bacteria.

Less soluble than primary bile salts.

The reabsorbed secondary bile acids are converted to primary bile acids and bile salts.

213
Q

Progressive Familial Intrahepatic Cholestasis (PFIC)

A
  • They are chronic autosomal recessive disorders causing hepatic fibrosis and end-stage liver disease.
  • This group of disorders is caused by the defects in bile secretion and/or absorption cause hepatic and systemic accumulation of bile acids and reduced enteric bile acid availability.
  • Clinical symptoms include history of neonatal diarrhea, sepsis and intermittent jaundice.

PFC1- Bile

PFC-2-BA

PFC3-PC

214
Q

Progressive Familial Intrahepatic Cholestasis 1

A

Byler disease- mutation in ATP8B1-encoding aminophospholipird flippase

Translocate: PS and PE (from outer inner leaflet)

•The deficiency of ATP8B1 in the hepatocyte results in the loss of asymmetric distribution of phospholipids in the canalicular membrane, decreasing both membrane stability and function of bile salt export pump (BSEP) and, as such, causing bile salt retention in hepatocytes with consequent defective bile formation; resulting in cholestasis.

215
Q

Progressive Familial Intrahepatic Cholestasis 2

A

•PFIC-2 is caused by mutations in the gene for bile salt exporter pump (BSEP) leading to retention of bile salts within hepatocytes.

The defective canalicular BSEP expression leads to bile secretory failure and retention of bile salts and other biliary constituents in the hepatocytes leading to progressive liver damage and cholestasis

216
Q

Progressive Familial Intrahepatic Cholestasis 3

Free bile acids cause cholangitis

A
  • PFIC-3 is caused by mutations in the gene for multidrug resistance protein 3 (MDR3) or floppase resulting in the lack of phosphatidylcholine in bile. (reduced PC in bile)
  • Free bile acids damage biliary epithelium causing a cholangitis; inflammation of the bile duct system.
  • Patients usually present in early childhood with cholestasis, jaundice, failure to thrive, and intense pruritus.
217
Q

diseases associated with bile acid metabolism

A

•Bile salts malabsorption can be caused by:

–Crohn’s disease, which is a type bowel inflammatory disease causing decreased bile salts absorption.

–Celiac disease is a long term autoimmune disorder primarily affecting the small intestine causing malabsorption.

–Chronic pancreatitis is associated with elevated fecal bile acids primarily due to their pH induced precipitation.

•High concentration of bile acids in the colon stimulates water secretion and chronic diarrhea.

218
Q

factors that maintain cholestrol solubility

A

phospholipids and bile salts

If cholestrol to phospholipids and bile salts ratio is more than 1:1 –> excess cholestrol crystalize

219
Q

Cholestrol Summary

A
  • Component of membranes and precursor of steroid hormones
  • Produced by most cells from Acetyl-CoA
  • Liver and intestines are the major producers
  • HMG-CoA reductase – rate-limiting step
  • Short- and long-term regulation
  • Primary bile acids are synthesized only in the liver
  • 7a-hydroxylase – rate-limiting step
  • Functions of bile acids, primary and secondary bile salts.
  • Cholesterol balance (enterohepatic circulation)
  • Gallstone formation.

Medical Biochemistry (12 decks)

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