Final Exam-Mahfouz Notes

Lipid Digestion/Absorption 1-16 Fatty Acid Oxidation 17-31 Ketogenesis 32-46 Fatty Acid Biosynthesis 47-78 Sphingolipid Metabolism 79-108 Protein Digestion 109-126 Amino Acid Degradation 127-149 Amino Acid Biosynthesis 150-160 Biosynthesis of Nitrogenous Compounds 161-167

What must happen to triacylglycerols in order to be absorbed?

they need to be hydrolyzed to FAs and glycerol

What happens during lipid emulsification?

the oil phase is broken down into microscopic droplets that are readily accessible to digestive enzymes in the GIT

Where does lipid digestion occur?

starts in the duodenum; the stomach contracts to stimulate the liver/pancreas to release enzymes (lipase and bile) that aid in digestion

What is lipase’s function in digestion? Bile?

lipase hydrolyzes the ester bonds in triacylglycerols to form glycerol and FAs

bile emulsifies lipids to speed up the lipase rxn and lipid digestion

How does lipase hydrolyze triacylglycerols?

lipase allows the molecules to enter (based on location) and get broken down via hydrolysis. There are three ester bonds in the molecule, so it has to undergo three hydrolysis reactions before it is completely broken down

aqueous media: closed active site

oil/water interface: open active site

Bile is stored in the ____ and made from ____ . They function in _____

liver, cholesterol, speeding up lipase reactions by emulsifying lipids

What is the purpose of emulsification?

to increase the oil/water interface and allow lipid digestion to occur much faster

What do intestinal cells do after absorbing FAs and glycerol?

re-esterify glycerol with FAs to re-assemble the triacylglycerols

emulsify the re-assembled triacylglycerols to prepare them for release into the main circulation

What is the function of intestinal cells?

break down absorbed lipids and cover them with apoproteins, creating lipoprotein particles

What are chylomicrons?

lipoproteins made by the intestine, they get released into the intestinal lymph vessels and then large blood vessels

What is the function of lipoprotein lipase?

to hydrolyze ester bonds within dietary triacylglycerols

What is the function of liver cells?

absorb chylomicron remnants via receptor mediated endocytosis and clear them from circulation

make its own lipids; lipids are emulsified into VLDL before getting released into circulation

import and destroy HDL particles

What is the main component of LDL and what happens when it enters the cells?

Cholesterol, once inside cells the LDL particles are destroyed and their cholesterol/triacylglycerol content is released into cytoplasm

What is cholesterol needed for?

to make cell membranes, excess is emulsified into HDL

What are the 2 parts of lipoproteins?

lipid part: emulsified lipids and phospholipids layer that surrounds them

protein part: apoproteins

What are the functions of each lipoprotein? (chylomicrons, VLDL, LDL, IDL, HDL)

chylomicrons: transport absorbed lipids from intestine to circulation

VLDL/LDL/IDL: transport lipids from liver to all body tissues

HDL: transport lipids from all body tissues to liver to be excreted in feces

What is produced when glucose is oxidized? Fatty acids?

carbon dioxide and water vapor

acidic byproducts that can accumulate in circulation

What is the purpose of acetyl CoA?

to start and maintain the citric acid cycle (provides cells with NADH and FADH2)

produces ATP when entering the oxidative phosphorylation pathway

What happens when glucose becomes scarce?

cells hydrolyze triacylglycerols stored in the adipose tissues to release FAs, which are oxidized to acetyl CoA to feed the citric acid cycle

What is the difference between saturated and unsaturated double bonds?

saturated have no double bonds in the hydrophobic chain

unsaturated have double bonds in the hydrophobic chain

What are the steps of FA activation for oxidation?

activation occurs in the cytoplasm when a FA is attached to a CoA molecule

activated FAs are transported to the mitochondria

FAs are oxidized in cycles, no more than 2 carbons are separated at the end of each cycle and the reaction consumes energy

What are synthetases?

a group of enzymes that use energy from ATP hydrolysis to link two smaller molecules to give a larger one

What are synthases?

enzymes that catalyze covalent bond formation between two molecules and do not require ATP

What is the function of acylCoA synthetase?

Activates FAs and hydrolyzes two high energy phosphate bonds to covalently link a CoA molecule to the fatty acid

What is needed so CoA can cross the mitochondrial membrane?

cartinine palmitoyl transferase (CPT1) removes CoA from activated FAs and replaces it with a carnitine molecule (becomes fatty acyl carnitine)

What happens once fatty acyl carnitine is in the mitochondria?

carnitine palmitoyl transferase 2 (CPT2) replaces carnitine with CoA and FA reactivates so it can be oxidized

When does fatty acid oxidation take place and what enzyme is needed?

when cells are deficient or lacking glucose

CPT1 allows FA oxidation, its activity is controlled by glucose metabolism

What happens in cells with an abundance of glucose? with no glucose?

part of the glucose is converted to malonyl CoA, an inhibitor of CPT1

if there is no glucose, malonyl CoA conc. drops and CPT1 is activated to turn on FA oxidation

What occurs in FA oxidation?

the long hydrophobic chain is broken down to acetyl CoA by adding a double bonded oxygen to carbon #3 (weakens the bond so it can be broken easier)

What are the four steps in an oxidation cycle?

• Dehydration

  • two hydrogens are removed from carbon 2/3 and a double bond is created between them so it can accept an oxygen atom; cofactor is FAD

• Hydration

  • a water molecule is added to the trans double bond of the unsaturated FA; does not require a cofactor or energy from ATP

• 2nd Dehydration

  • Hydroxyacyl CoA dehydrogenase removes an H from the OH on carbon 3 and an H from carbon 3 to create a double bond between the two atoms; uses NAD as a cofactor and produces NADH and a hydrogen

• Thiolysis

  • the bond between carbon 2/3 is broken by inserting a CoA molecule via thiolase; does not require a cofactor or energy from ATP but uses sulfur instead

  • the FA is split into two fragments

What is a dehydrogenase?

an enzyme that removes hydrogens and catalyzes dehydrogenation reactions, require a cofactor (1st FAD 2nd NAD)

What is a hydratase?

an enzyme that adds a water molecule to a double bond

What is the energy yield from FAs?

acetyl CoA generates 3 NADH and 1 FADH2 (GTP is generated when succinyl CoA gets converted to succinate

one acetyl CoA is equivalent to 12 ATPs

What is the function of dehydrogenases?

remove hydrogens

What is the function of reductases and what cofactors do they require?

adds hydrogens; requires NADH or FADH2 as a cofactor

What is the function of carboxylase and what do they require?

adds a carboxyl group via CO2 or HCO3, requires ATP and biotin (B7) as cofactors

What is the function of racemase?

an enzyme that interconverts between the R and S isomers of chiral molecules, does not require cofactors or ATP

What is the function of mutase and what does it require?

shifts functional groups form one carbon to the directly adjacent carbon, requires cyanocobalamin (B12)

The ATP yield from succinyl CoA is ____ than acetyl CoA because it enters half-way through the cycle

less

The number of enzymes needed for and oxidation cycle depends on the number of ____ present

double bonds

one double bond: one additional enzyme

more than one double bond: three enzymes

Why can’t brain cells oxidize FAs to acetyl CoA?

they do not make the enzymes needed, they instead use ketone bodies

if neither glucose or ketone bodies are available, the brain shuts down and the person goes into a coma

When/where does ketogenesis occur and what is its purpose?

when glucose levels drop, occurs in the mitochondria of liver cells

provides ketone bodies for brain cells to maintain the CAC and make ATP

what are examples of ketone bodies?

acetoacetate, beta-hydroxybutyrate, and acetone

Ketone bodies are acidic because they have a ____

carboxyl group; large amounts can overwhelm blood buffers and cause systemic acidosis

What reactions occur during ketogenesis?

• 1st condensation

  • two acetyl CoA molecules combine to give acetoacetyl CoA, catalyzed by thiolase in a reversible reaction

• 2nd condensation

  • a third acetyl CoA is added to produce HMG CoA, catalyzed by HMG CoA synthase (no ATP)

• HMG CoA split

  • HMG CoA is split into acetyl CoA and acetoacetate, catalyzed by HMG CoA lyase

  • part of acetoacetate is absorbed by the brain, the other part is reduced by beta-hydroxybutyrate dehydrogenase to give beta-hydroxybutyrate

What is the function of ketoacyl CoA transferase and what does it require?

it converts acetoacetate to acetoacetyl CoA

requires succinyl CoA to catalyze the reaction and produces acetoacetyl CoA and succinate

What is the function of the produced succinate?

it feeds the CAC and produces 6 ATPs via biosynthesis as well as acetoacetyl CoA

In relation to ketogenesis, what happens in patients who don’t take their insulin?

they experience a shift in metabolism for FA oxidation, severe cases cause a drop in pH and eventually systemic acidosis

As glucose levels rise insulin is released to allow absorption and conversion to ______

acetyl CoA

What enzyme does insulin inhibit and what effect does this have?

HS lipase in adipose tissue; stops the hydrolysis of triacylglycerols

When the liver is saturated with glycogen, what happens to the excess glucose in circulation?

it is absorbed by adipose tissue and converted to FA, which are esterified to glycerol to make triacylglycerols for storage (unlimited in adipose)

What are FAs used to make?

lipids and cell membranes

How are FAs made?

cells use malonyl CoA to elongate the hydrophobic chain on acetyl CoA

oxidation occurs in the mitochondria, biosynthesis occurs in the cytoplasm

What is FA degradation activated by and what cofactor(s) are needed?

activated by acetyl CoA

cofactors are FAD+ and NAD

What is FA biosynthesis activated by and what cofactor(s) are needed?

activated by ACP

cofactor is NADPH

What is the function of acetyl CoA carboxylase? What cofactor does it require?

it allows cells to convert acetyl CoA in the cytoplasm to malonyl CoA

requires biotin (B7) as a cofactor

What compounds activate acetyl CoA carboxylase?

insulin (helps store excess glucose)

citrate (made when glucose is abundant)

What compounds inhibit acetyl CoA carboxylase?

glucagon/epinephrine (inhibits nutrient storage)

palmitoyl CoA (feedback inhibition)

What must occur for activation in FA biosynthesis?

attaching to the acyl carrier protein (ACP)

the activating enzyme attaches the FA to a sulfur atom at the end of a long hydrophobic chain made from vitamin B5

What compound do both CoA and ACP require to function?

pantothenic acid (vitamin B5)

What are the steps of hydrophobic tail elongation? How many carbons are made per cycle?

Condensation

Reduction (reductase, cofactor)

Dehydration (dehydrase enzyme, no cofactor)

Reduction

2 carbons per cycle

The default FA is _____

palmitic acid

How are FAs with more than 16 carbons elongated?

the FA is transported to the ER and activated by COA

2 carbons are added from malonyl CoA (elongase)

What are elongases?

enzymes that elongate the hydrophobic chain

How are unsaturated FAs made?

cells start with the saturated portion of the enzyme and desaturase removes hydrogens to create double bonds (not beyond carbon #9)

Human desaturases cannot remove hydrogens beyond carbon #9. What are FAs with double bonds beyond carbon #9 called?

essential FAs

What is an example of an essential FA and what is it used for?

arachidonic acid

used to make eicosanoids, which are needed for the inflammatory response

Triacylglycerols are storage molecules, so their biosynthesis pathways are only activated when nutrients are _____

plenty

What reactions occur when FAs are esterified to glycerol and stored in adipose?

glucose in circulation triggers insulin release

insulin activates acetyl CoA carboxylase

malonyl CoA elongates the FA hydrophobic chain (depending on desired # of carbons)

glycerol is made from glucose and is esterified by FAs to make triacylglycerols

What must happen before esterification can occur?

glycerol and FAs need to be activated

How is glycerol activated? FAs?

glycerol: activated by phosphorylation, becomes glycerol-3-phosphate

FAs: activated by attaching CoA

What is the function of kinases?

adding phosphate groups

________ is produced after two esterification steps of glycerol

phosphatidic acid

True or False: the first hydroxyl, R1 is saturated

true

True or false: the second hydroxyl, R2, is saturated

false

In the diagram, what is the charged state of the phosphate group (X)?

charged/uncharged, polar

What are the various functions of insulin?

secreted when glucose is high

decreases cAMP (eventually stops FA release)

activates pyruvate dehydrogenase (acetyl CoA is made and converted to citrate)

activates acetyl CoA carboxylase (makes malonyl CoA)

Malonyl inhibits ____ and is used to make ____

FA oxidation, FAs

Sphingolipids are membrane lipids found in _____

nervous tissue

What are ceramides made of?

a sphingosine molecule covalently link to a FA through an amide bond

What are sphingomyelins made of?

ceramides with a phosphocholine group linked to sphingosine’s OH group

What are cerebrosides made of?

a ceramide with a single carbohydrate bond linked to sphingosine’s OH group

What are gangliosides made of?

a ceramide with a multiple carbohydrate bonds linked to sphingosine’s OH group

How are ceramides made?

by condensing together palmitic acid and serine

1. Condensation: catalyzed by synthase, no ATP

2. Reduction: addition of hydrogen, cofactor is NADPH

Sphingolipids are broken down in _____ by _____

lysosomes, hydrolyzing enzymes

What is the final product of sphingolipid degradation?

FAs and sphingosine (these are safe but their intermediates are cytotoxic)

What is cholesterol used to make?

bile salts (50%) and steroids (10%)

What is the precursor for cholesterol?

acetyl CoA

What are the three steps of cholesterol biosynthesis?

condensation of three acetyl CoA molecules to isoprenoid intermediates

condensation of isoporene intermediates into squalene

cyclization of squalene to cholesterol

What are the sources of cholesterol?

endogenous (made by the body) and exogenous (obtained from diet)

Dietary cholesterol is absorbed by intestinal cells and incorporated into ____ particles, which are packaged into _____ particles and released into circulation

chylomicron; VLDL

What process is used to absorb LDL particles?

receptor mediated endocytosis

How are LDL particles absorbed?

LDL receptors (clathrin coated pits) identify the particles by binding to the ApoB protein and then import them into the cytoplasm

What is the body’s response to a cholesterol rich meal?

LDL levels rise, which inhibits the HMG CoA reductase enzyme and stops cells from making their own cholesterol

Cholesterol also stops ribosomes from making the HMG COA reductase enzyme

What are the two groups of cholesterol lowering drugs?

statins ex: Lipitor (inhibit HMG CoA)

resin molecules ex: Zetia (block intestinal absorption of dietary cholesterol)

What are the biological roles of the steroid hormones? (androgens, estrogens, progestins, glucocorticoids, mineralocorticoids)

androgens: male sex hormone

estrogens: female sex hormone

progestins: regulate events during pregnancy

glucocorticoids: anti-inflammatory

mineralocorticoids: regulate salt/water retention

Eicosanoids are biologically _____ FAs and are made from ______.

active; arachidonic acid

The action of eicosanoids is _____ and they are synthesized by ______

localized; all cells (except RBCs)

What is the function of prostaglandins?

inflammatory response (tissue swelling, pain, fever)

What is the function of thromboxanes?

platelet aggregation and blood clotting