Medical Biochemistry I-Exam 2 – Flashcards

driven directly by release of energy

ATP hydrolysis

driven by large favorable gradient but the molecule described moves against a small unfavorable gradient

uses energy derived from pumping other ions to fuel its own movement

insulin and glucagon

insulin is released in response to high blood glucose and brings blood glucose levels down

glucagon is released in response to low blood glucose levels and brings blood glucose levels up

glucose

glycogen

glycolysis accompanied to TCA cycle coupled with oxidative phosphorylation

glycolysis diverted to form lactic acid

gluconeogenesis

liver

brain

b/c liver is so impt to metabolism

Other organs can interconvert molecules to make fats

Fatblox can inhibit the transport of lipid signaling molecules by binding to them, preventing them from reaching their targets, could cause problems

In order of work rate (from high to low):

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free ATP

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Creatine Pi

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glycolysis

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fatty acids

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membrane receptors-cause intracellular stimulation

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intracellular receptors-affect gene regulation

H1 located in endothelium and smooth muscle and causes a vasodilation effect when acted upon by an antagonist (Claritin Allegra)

Acts on sinus and allergy

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H2 receptor is located in the stomach and causes a decrease in gastric acid secretion when acted upon by an antagonist (Zantac)

cAMP formation and phosphorylation

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cAMP turned on by cyclases

turned off by phosphodiesterases

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phosphorylation by kinases

turned off by phosphatases

receptor inactivation by phosphorylation

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receptor internalization

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receptor degradation

No, pathways are independent on each other

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They inhibit one pathway and pick up slack on other pathway

aerobic - pyruvate

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anaerobic - lactate

phosphorylate glucose to glucose-6-phosphate

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enzyme - hexokinase (in all tissues)

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or

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glucokinase (only in liver)

enzyme - phosphofructokinase-1

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fructose-6-phosphate ;fructose-1,6-bisphosphate

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ATP is not generated in this step, but is used to transfer Pi to fructose-6-phosphate

Phosphofructokinase-1 is committed step and heavily regulated by enzymes.

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IN MUSCLE

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In muscle, phosphofructokinase-1 is inhibited by citrate and increased levels of ATP.

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AMP, ADP, cAMP, and Pi reverse the inhibitory affects of ATP on PFK-1.

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Another control is from the synthesis of pyruvate and ATP from PEP and ADP. In muscle, pyruvate kinase is feedback inhibited by ATP.

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IN LIVER

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fructose-1,6-bisphosphatase will remove phosphate from f-1,6-bisphosphate, converting it backwards into fructose-6-phosphate. Phosphatase is also monitored.

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Fructose-2,6-Phosphate (vasopressin and phenylephrine promote its synthesis) will inhibit this enzyme from removing the phsophate, thus activating PFK-1 when blood glucose is low. Fructose-2,6-Bisphosphate acts as a competitive inhibitor of fructose-1,6-bisphosphatase, inhibiting it from deposphorylating F-1,6-Bisphosphate and increasing the flux of F-6 Phosphate through PFK-1. Glucagon controls F-2,6-bisphosphate, stopping glycolysis and enhancing gluconeogenesis.

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Another control is from the synthesis of pyruvate and ATP from PEP and ADP. In liver, pyruvate kinase feedback is inhibited by ATP and positively affected by fructose-1,6-bisphosphate.

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2 steps:

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1) 1,3-bisphoshoglycerate;3-phosphoglycerate

(phosphoglycerate kinase)

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1 ATP produced.

;

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2) PEP;pyruvate

(pyruvate kinase)

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A total of 4 ATP (2 net ATP are produced) from glycolysis. 2 ATP are used up during the glycolysis process.

3 steps:

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PEP→Pyruvate

F6P→F-1,6-BP

Glu→G6P

gluconeogenesis uses enzymes specific to glucose synthesis

Certain processes are localized to certain cellular compartments

mitochondria

ER

Mitochondrial matrix.

The malate shuttle is when oxaloacetate is changed to malate so it can be transferred across the mitochondrial membrane.

conversion of glucose-6-phosphate occurs in the lumen of the ER.

There is a series of transporter proteins that play an integral role in the conversion of glucose.

1) T1 translocase pumps G-6-Phosphate into the lumen of the ER. The phosphatase for converting G-6-Phosphate lies in the lumen.

2) After dephosphorylation, the dissociated Pi is removed from the lumen into the cytosol by T2 translocase. T2 requires Ca to pump out Pi. A separate channel allows Ca to flow in the ER lumen.

3) glucose is pumped out of ER to cytosol by T3 translocase.

PPP does not produce or utilize any ATP, but NADPH (reducing agent) is produced

NADPH produced in oxidative reactions of G6P and 6-phosphogluconate.

1) produce reducing agents, NADPH, for cytosolic rxns

2) produce ribulose-5-phosphate for nucleotide synthesis

3) provide alternative method for metabolizing glucose

4) allow for interconversion of pentoses and hexoses

Rate limiting step

glucose-6-phosphate converted to 6-phosphoglucono-δ-lactone by glucose-6-phosphate dehydrogenase.

Glucose-6-dehydrgoenase is inhibited by NADPH and activated by ↑ NADP+ (substrate availability)

Reduced glutathione in RBCs react with peroxides to form glutathionedimers. Glutathione can prevent oxidative damage to RBCs. NADPH is used to break up glutathione dimer in the cell and restore glutathione levels to react with other peroxides.

A deficiency in glucose-6-phosphate dehydrogenase can't produce enough NADPH to restore glutathione levels.

This has 2 effects:

1) peroxides build up and damage RBC membranes

2) Heinz bodies (cross linkings of Hb) will reduce Hb flexibility, causing rupture of now fragile hemoglobin that is passed through small vesssels.

Weakened membranes and Heinz bodies will lead to acute hemolytic anemia, black urine, and increased urine flow (compensation to reduce renal damage from lysed RBCs)

Carried out in tissues with high amts of oxidation such as erythrocytes and leukocytes. Essential is nucleotide synthesis (gastric mucosa, bone marrow, and skin). Frequently occurs in tissues heavily involved in lipid and catecholamine synthesis (adipose, liver, lactating mammary, adrenal cortex, nervous system)

Takes place in the cytoplasm.

skin cells

bone marrow

gastric mucosa

generally tissues with a high rate of turnover of cells

liver

adrenal cortex

lactating mammary

adipose

nervous system

erythrocytes

leukocytes

3 categories

1) oxidative rxns

2) isomerization or epimerization rxns

3) rxns that require C-C bonds to be cleaved or formed

ATP

bicarbonate

acetyl CoA

acetyl CoA in mitochondrial matrix combined with OAA to form citrate

citrate is transported via a transporter from the mitochondria into the cytosl

citrate lyase using CoA cleaves citrate, into OAA and acetyl CoA

1) acetyl CoA + enzyme → acetyl-Enz by acetyl transferase

2) malonyl CoA + ACP → Malonyl-ACP by malonyl transferase

3) acetyl-enz+malonyl-ACP → acetoacetyl-ACP by keto synthase or condensing enzyme

4) acetocetyl-ACP → beta-hydroxybutyryl-ACP by beta-ketoacyl ruductase

5) beta-hydroxybutyryl-ACP → crotonyl-ACP by dehydratase

6) crotonyl-ACP → butyryl-ACP by enoyl reductase

7) butyryl-ACP → palmitoyl-ACP using 6 more malonyl coA in 6 rounds of steps 1-6

8) palmitoyl-ACP → palmitic acid by thioesterase

capric (C10)

lauric (C12)

myristic (C14)

easier to digest compared to palmitate for sucking infants

linoleic (18:2)(9,12)

linolenic (18:3)(9,12,15)

fatty acids are acylated by condensing with CoA to form Fatty acyl CoA

3 fatty acyl CoAs are then esterified to glycerol-3-phosphate to eventually form triglycerides (also called triacylglycerol)

FADH2

NADH

acetyl CoA

racemase

methy malony CoA mutase

propionyl CoA carboxylase

acetyl CoA carboxylase

allosteric activator - citrate

inhibitor - fatty acyl CoA

methylmalonyl CoA mutase is missing

conversion of Vitamin B12 into coenzyme is missing

natural inhibitor compound - cerulenin

artificial inhibitor compound - C75

blood concentrations of acetoacetic acid and beta-hydroxybutyric acid are as high as 20 mM.

These compounds are strong acids with a pKa of ~3.5, resulting in acidosis

In biochemical terms, the events are very similar to starvation mediated ketosis:

a) increased glucagon/insulin ratio results in elevation of liver cAMP

b) Elevated liver cAMP leads to decreased malonyl CoA

c) decreased malonyl CoA leads to de-inhibition of CPT I

d) de-inhibition of CPT I results in activation of fatty acid oxidation (fatty acid degradation) and increased ketone body production

alcohol dehydrogenase

aldehyde dehydrogenase

ω-methyl

adjacent methylene carbon of fatty acids

fatty acids 6-10 Cs long

Capric acid = C₁₀ -  4 NADH + 4 FADH₂ + 5 Acetyl CoA = (4x3) + (4x2) + (5x12) = 80 ATP

Adipose storage of TAG’s initially uses less energy to produce TAG’s, plus, degradation via ß-oxidation provides

            more energy/ ATP than Glycogen storage

ketone bodies are synthesized by liver during starvation to feed the brain

acetoacetate is converted to acetoacetyl CoA by thiophorase after cross blood brain barrier

acetoacetyl CoA can be converted to 2 acetyl CoA by thiokinase

2 acetyl CoA then undergo citric acid cycle to produce energy in the brain

defect in transporting fatty acid carnitine

don't have free fatty acids to make acetyl CoA and subsequently don't get ketone bodies

don't make enough ketone bodies

bile salts

vitamin D

corticosteroids

sex hormones

1.)  Mevalonate synthesis → Mevalonate

2.) Isoprenoid synthesis → Isoprenoid units

3.) Squalene synthesis → Squalene

4.)  Lansterol Synthesis → Lansterol

5.)  Synthesis of Cholesterol from Lanosterol → Cholesterol

rate limiting step

HMG-CoA + 2 NADPH + 2 H+ → Mevalonate + 2 NADP+ + CoASH

1.)  Bicyclic control system:

      As insulin ↑ ­, cholesterol ­↑

      As glucagon ↑ ­, cholesterol ↓

2.)  HMG-Reductase degradation:

As cholesterol ↑ ­HMG-Reducases downregulates.

3.)  Genetic controls:  Sterols and mevalonate metabolites inhibit HMG-Reductase RNA synthesis

meat

dairy

poultry

The body metabolizes some cholesterol into bile salts and steroids.

Rest go to tissues for storage or excreted out of body in feces.

modification of cholesterol by ring hydrozylations and side chain oxidation result is cholic acid

cholic acid reacts with amino acids to form amides known as bile salts

Fxn: released by gall bladder to help solubilize dietary fats

Liver  → Gall bladder storage → Intestine (some to lymphatics) →  Bloodstream → Liver.

1) inhibition of HMG-CoA reductase; Mevacor

2) in small intestine removal and excretion of bile salts; Colestipol or Cholestyramine

angiotensin

bradykinin

epinephrine

thrombin

Eicosanods: Latin for “20” (number of C atoms in the molecules)

Prostaglandins:  Thought to be from the prostate gland

Thromboxanes:  Isolated from platelets

Leukotrienes:  Isolated from leukocytes

glycerophospholipid → arachidonic acid

cyclooxygenase reaction of arachidonic acid → thromboxane or prostaglandin

lipoxygenase reaction of arachidonic acid → leukotriene

aspirin

non-steroidal anti-inflammatory drugs (NSAIDS)

8 EFFECTS

stimulate smooth muscle contraction

regulate steroid synthesis

inhibit gastric secretion

inhibit hormone sensitive lipases

inhibit platelet aggregation

regulate nerve transmissions

sensitive to pain

mediate inflammatory response

leukocytes

mast cells

vascular tissue

platelets

macrophages

contraction of smooth muscle in pulmonary airway

alteration in permeability of microvasculature, resulting in fluids and proteins leaking into tissues

↑ NADH levels indicate excess energy; therefore, ß-oxidation of triacyglycerols doesn't occur resulting in high lipid levels

ω-3 = Omega-3 Fatty acids = Fatty acids with a double bond 3 carbons away from the last (ω) carbon on the F.A. chain

                   Example = Linolenic acid 18:3 (9,12,15) 

         ω-6 = Omega-6 Fatty acids = Fatty acids with a double bond 6 carbons away from the last (ω) carbon on the F.A. chain

                   Example = Linoleic acid  18:2 (9,12)

1) 2 molecules of acetyl CoA → acetoacetyl CoA (thiolase)

2) acetoacetyl CoA → HMG CoA

(HMG CoA synthase)

3) HMG CoA → Acetoacetate + Acetyl CoA

(HMG CoA lyase)

4a) Acetoacetate → Acetone

(Spontaneous)

or

4b) Acetoacetate → Beta-Hydroxy Butyrate

(dehydrogenase)

Ketogenesis occurs before

Acetoacetate

1) Acetoacetate → Goes Through Blood to Tissue

2) Acetoacetate + succinyl CoA → Acetoacetyl CoA

(thiophorase)

3) Acetoacetyl CoA → 2 Acetyl CoA

(thiokinase + CoA)

4) 2 Acetyl CoA enter TCA cycle to produce energy

SEE PAGE 67

Yes, muscles can use ketone bodies as energy source

2) Acetoacetate + succinyl CoA → Acetoacetyl CoA

(thiophorase)

3) Acetoacetyl CoA → 2 Acetyl CoA

(thiokinase + CoA)

4) 2 Acetyl CoA enter TCA cycle to produce energy

↓ Insulin production = ↑[Glucagon]/[Insulin] ratio, hence, F.A.’s will be mobilized via Hormone sensitive Lipase. 

Due to ↓ Insulin, there will be an increase in F.A. ß-oxidation producing an overabundance of Acetyl CoA, which is then converted into Ketone Bodies.  The [Ketone Body] ↑, and because these compounds contain highly acidic protons (pKa = 3.5), the blood pH will become acidic = DKA.