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246 Cards in this Set

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Alternate Names for Pentose Phosphate Pathway
-Hexose Monophosphate Shunt

-6-Phosphoroglucontate pathway
Pentose Phosphate Pathway Products
NADPH for reductive biosynthesis
-fatty acids and steroids

-Nucleic Acids

Glycolytic Intermediates
Adenine nucleotides and energy charge reciprocally regulate
catabolic and anabolic pathways

Glycolysis to
Pyruvate Dehydrogenase to

Tricarboxylic Acid Cycle
Negative and Positive for Glycolysis, Pyruvate Dehydrogenase, and Tricarboxylic Acid Cycle in PPP
Negative: NADH, ATP

Positive: NAD+
Oxidative Phosphorylation in PPP


Higher requirement for NADPH than
ribose-5-phosphate- complete oxidation of G6P to CO2 and resynthesis of G6P and ribulose-5-P.

Higher requirement for ribose-5-P than
NADPH, G6P is converted to fructose-6-P and glyceraldehyde-3-P by glycolytic pathway

PPP to
NADPH (Coemzyme for reductive biosynthesis)

to Sugar Interconversions (ribose-5-P for nucleotides)
PPP Stage I
Generates 2 pairs of e-
Start: Glucose-6-P

End: Ribulose-5-P

Decarboxylation of hexose to pentose yielding NADPH. IRREVERSIBLE
PPP Stage II
Start and end with 5C

Interconversions of pentose-Ps
leads to glycolytic
Glucose-6-Phosphate Dehydrogenase
Catalyzes the first step in the pentose phosphate pathway

Rate limiting step- Glucose-6-phosphate to 6-phospho-gluconate

Uses NADP as a cofactor (reaction generates NADPH)

Highly regulated by NADPH/NADP ratio
Cellular Feedback Mechanism

NADPH/NADP = high = inhibits G6PD

NADPH/NADP = low = activates G6PD
Primarily uses high energy electrons for biosynthesis

Fatty Acids
(Reduced Form)

Uses high energy electrons to make energy (ATP via oxidative phosphorylation)
Functions of NADPH
Provide high energy electrons for reductive
Used as a cofactor by enzymes that deal with
reactive oxygen species (ROS)

NADPH has a uniqure role in biosynthesis b/c the pthwy & direction of glucose-6-phosphate is determined by the needs of the cell for NADPH or sugar intermediates

These functions cannot be replaced by NADH
Reactive Oxygen Species - Bad Species

Highly reactive O2 and H2O2

Can break strands of DNA & when ody repairs, can cause mutations
genetic mutation
ROS and Lipids
membrane function
ROS and Protein
enzyme inactivation
Superoxide Anion-produced biologically by
a variety of reactions most notably by “leaky”
mitochondrial electron transfer. Electrons can be Transferred from the reduced form of
Coenzyme Q to oxygen, thus generating superoxide
Hydrogen Peroxide: produced by oxidase enzymes. Very toxic organic peroxides can be formed from 2e- reduction of O2 in compounds containing double bonds (unsaturated fatty acids).
Hydroxyl Radical: produced from a metal catalyzed reaction of superoxide and hydrogen peroxide. Very reactive species that can take part
in free radical chain reactions.

What is it and function
A Multifunctional Peptide

Function: Major cellular reductant and suflhydryl
buffer, conjugated to drugs to make them more soluble, amino acid
transport across membranes, disulfide interchanges in proteins.
Cellular Defense Against Oxidative Stress

Superoxide Dismutase (SOD)-detoxifies superoxide
2H+ + 2O2- H2O2 + 2 O2
MnSOD (mitochondrial enzyme)
Cu-ZnSOD (cytoplasmic enzyme)- enzyme deficiency leads to
Severe progressive neurodegenerative disorder:
Lateral Sclerosis (ALS) or Lou Gherig’s Disease
Cellular Defense Against Oxidative Stress

Catalase-heme containing peroxidase that detoxified H2O2
2H2O2 2H2O + O2
Cellular Defense Against Oxidative Stress

There are no known enzymatic systems that deal directly
With hydroxyl radicals. Cells rely on the above two reactions
To remove precursors to ROS>
Cytochrome P-450 System
Liver enzymes detoxify many nasty compounds:


These enzymes require NADPH as a cofactor.
Clinical Correlation: Glucose-6-P Dehydrogenase (G6PD) Deficiency
Lack of G6PD results in loss of NADPH production, loss of Glutathione antioxidant system, increased oxidative stress,
Membrane damage and red blood cell lysis.

X-linked disease is the most common disease causing enzymatic
defect in humans (200 million people world wide).
Hemolytic anemia caused by this mechanism can be precipitated by oxidant drugs (e.g., primaquine), diet (fava beans), infection
(induction of NADPH Oxidase).
G6PD Mutations
Slightly decreased life span (complications from hemolysis).

Many mutations alter G6PD function.

Many alter the Km and Vmax of the enzyme

Some mutations confer resistance to flaciparum malaria

3 major drug markets: US, Europe, Asia
Drugs that Exacerbate G6PD
e.g., sulfamethoxazole

e.g. primaquine,

e.g. acetanilide (should not be used) NOT aspirin or acetaminophen
Pentose Phosphate Pathway Summary
Pentose Phosphate Pathway
-NADPH, Ribose-5-phosphate, other 3-7 carbon carbohydrate interconversions.

Role of NADPH
-Reductive Biosynthesis
-Required for enzymes (glutathione reductase) that deal with reactive O2 species.

Mutations in the rate-limiting enzyme G6PD
Glucuronic Acid
Importance: Glucuronic acid is conjugated to endogenous and exogenous compounds producing a strongly acidic compound that is more water soluble at physiological pH than its precursor.

Important in (LIVER): Drug detoxification
Steroid excretion
Bilirubin metabolism
Glucuronic Acid Synthesis
Start: glucose
End: D-Glucuronic acid

Many intermediates
Lipid: location and function
Most contain or derived from fatty acids
Many functions:
a) major fuel store
b)constitute membranes
c) solubalize nonpolar substance in bodily fluids (bile acids)
d) important signaling molecules (scosiniods/prostaglandins)
Fatty Acid Structure
Alkyl chain with a terminal carboxyl group R-COOH

Saturated CH3(CH2)nCOOH

Unsaturated (up to 6 double bonds) bent shape

Most akyl chains have an even number fo carbon atoms usually 12-24
Numerical Formulas
Show number of carbon atoms, number of double bonds, and bond location starting with carboxyl carbon.
Nervonic acid 24:1(15)

Count from Omega end
Triacylglycerols (TAGs)
Three fatty acids esterified to a glycerol backbone

On a weight basis, pure TAG yields 2.5 times more ATP than pure glycogen

TAGs can be stored without associated water, thus decreasing the storage weight.
Digestion and Absorption of Lipids
Adults ingest 60-150 gm of lipid/day. Triacylglycerols constitute 90% of dietary fat.
Other 10% are phospholipids, cholesterol, cholesterol esters, and free fatty acids.
From least to most:

Chylomicron, VLDL, IDL, LDL, HDL
Lipoproteins in Liver & Intestine
generate HDL

Lowest TAG, high cholesterol

Deliver cholesterol to liver for elimination
Lipoproteins in VLDL (very low density lipids)

Low TAG, Highest cholesterol

Deliver cholesterol to peripheral tissues and liver
Lipoproteins in Liver
generates VLDL

High TAG, low cholesterol

deliver de novo TAG to peripheral tissues
Lipoproteins in Intestine
generates Chylomicron

Highest TAG, lowest cholesterol

Deliver dietary TAG to peripheral tissues
Lipid Transport in Fed State
Liver TAGs :
FA synthesized from excess carbohydrate and amino acids

FA assembled into TAGs, packaged into VLDL, secreted into the blood stream (chylomicrons to cytoplasm)

VLDL and chylomicrons are hydrolyzed by lipoprotein lipase (endothelial cells in muscle and adipose tissue) ApoC-II (apoprotein lipase) activates binding

products (FA & glycerol) taken up reassembled to TAG (adipose), or used as fuel (muscle)
Mechanisms if fed state vs fasted state
more feedback mechanisms in the fasted state
Lipid Transport in Fasted State
TAGs in adipose mobilized
Hormone-sensitive lipase activated by phosphorylation by cAMP-dependent protein kinase A

Perilipin not phosphorylated blocks lipase access to TAG (hormome sensitive)

Once hydrolysis complete, FAs and glycerol released into the blood. FAs transported by serum albumin

PROLONGED fasting liver makes ketone bodies, acetoacetate and b-hydroxybutyrate
Fatty Acid Biosynthesis
Occurs in the cytosol

Palmitic acid (C16H32O2) is first synthesized from carbohydrate intermediates, amino acids and other fatty acids.

All other fatty acids are made by modification of palmitic acid.

Acetyl CoA provides all the carbons for FA synthesis in two carbon units.

Sequence of reactions is carried out by fatty acid synthase.
Transfer of Acety CoA from mitochondria to cytosol for fatty acid biosynthesis by the citrate cleavage pathway
Occurs in mitochondria

Pyruvate can't cross. Must be converted to citrate

Citrate Synthase is the 1st citric acid cycle step
Acetyl-CoA carboxylase
Biotin is a coenzyme
-Requires 1 molecule of ATP and HCO3
-Biotin is a coenzyme that transfers the CO2 to Acetyl-CoA to yield malonyl-CoA
-Key control point for fatty acid synthesis
-Citrate is an allosteric activator
-Palmitoyl CoA is an allosteric inhibitor
-Glucagon and cAMP promote inactivation by AMP-mediated phosphorylation
-Dephosphorylation activates Acetyl-CoA Carboxylase
-Diet controls pathway by regulating enzyme synthesis
Mammilian Fatty Acid Synthase
Multienzyme polypeptide that is composed of 2 identical subunits
How do we release palmetic acid?
Palmitoyl-ACP acted on by thioesterase to produce palmitic acid

Both sulfhydryl groups of synthase and ACP are free, so another round of FA synthesis can begin
Characteristics of Fatty Acyl Synthase
It is essential, but not rate limiting

Not subject to short term control

All activities on a single contiguous protein

In animals, the synthase is active only as a dimer
Palmitate Modifications for Formation of Other Fatty Acids
-Elongation of Fatty Acids
Occurs in the endoplasmic reticulum (from maloyl CoA) or mitochondria (from Acetyl CoA)

-Desaturation of Fatty Acids
Occurs in endoplasmic reticulum (enzyme is monoxygenase)

-Hydroxylation of Fatty Acids
Occurs in mitochondria of many tissues
Occurs in tissues of the nervous system where long chain fatty acids are needed (C22 and C24)
Pathway of fatty acid elongation in mitochondria
Preferred substrate is palmitoyl CoA

Intermediates are acetyl-CoA esters

Converts palmitate to stearate for tissues except the brain. Chains are extended up to C24

NADH and NADPH serve as reducing agents
Desaturation of Fatty Acids
Requires the combination of desaturase enzyme,
cytochrome b5 and NADPH-cytochrome b5 reductase.

Occurs at C 4,5,6,9
Unsat fatty acids essential to humans
US has a lower MP and liguid at RT
Fatty acids usually stored as triglycerides
Storage of fatty acids as triacylglycerols
Structure of TAG

Synthesis of glycerol phosphate

Free fatty acid is converted to activated form (usually attached to Acetyl CoA)

Triacylglycerols are synthesized from Fatty Acyl CoAs and Glycerol 3-Phosphate
Synthesis of Triacylglycerols
Formed by activated fatty
acids and products of glucose

The first step is formation of phosphatidic
Synthesis of Triacylglycerols cont
Fed State: Glycolysis
Fasted State: Pyruvate
Backbone of TAG: glycerol-3-phosphate
1st step: lysophosphatidic acids
Synthesis of Triacylglycerols cont
Activated form of fatty acid: fatty acyl CoA pool
Complex Lipids: Sphingomyleins and glycerol phosphlipids
Synthesized: Triacylglycerols
Carnitine Transport of Acyl Groups Across the Inner Mitochondrial Membrane
Fatty acyl CoAs are formed outside mitochondria.

Oxidizing enzymes are located in the inner mitochondrial membrane

Membrane is impermeable to CoA

Carnitine is the transport molecule for fatty acids into the mitochondrial matrix. Oxidation of FA occurs here.
Carnitine Mediated Transport of Fatty Acids into Mitochondria for Oxidation
1.) Fatty acid transferred to carnitine by carnitine-palmitoyl transferase (CPTI) to yield acylcarnitine.

2.) Acylcarnitine is translocated across the inner mitochondrial membrane by translocase.

3.) Fatty acid is transferred to CoASH by CPTII and carnitine is recycle back to the intermembrane space to react with another fatty acid.
Fatty Acid b-Oxidation
FAS are oxidized sequentially 2 carbons at
a time.
Sequential steps are:

Oxidized while attached as a thioester to
4-phosphopantetheine of CoA.

Each set of oxidations produces:
-1 acetyl-CoA-10 ATPS
-1 FADH2- 1.5 ATPs
-1 NADH- 2.5 ATPs
Overall yield of Fatty Acid b-Oxidation
Oxidation of palmitate yields 7 oxidations
with 1 acetyl CoA as the final product. The
Overall yield is (7X14ATPS) + 10 ATPS-
(2ATPS for palmitate to palmitate-CoA)=
106 ATPS.
Additional Enzymes
b-oxidation oxidizes saturated fatty acids with even number
Odd-chains produce propinolyl CoA
Unsaturated fatty acids require additional enzymes

a- oxidation is necessary for metabolism of branched chain fatty acid, uses fatty acid a hydroxylase (Refsum disease) occurs in peroxisomes - Rare b/c not in mitochindria
Subcellular location: Cytosol

Carriers of acyl/acetyl groups: Citrate

Acyl carrier: Acyl Carrier protein

Activator: Citrate

Inhibitor: long-chain fatty acyl CoA

Product of pathway: Palmitate

Repetitive four-step process: Condensation, reduction, dehydration, reduction
Subcellular location: Mitochondria

Carriers of acyl/acetyl groups: Carnite

Acyl carrier: CoA


Inhibitor: Malonyl CoA

Product of pathway: Acetyl CoA

Repetitive four-step process: Dehydrogenation, hydration, dehydration, thiolsis
Ketone Bodies: an alternate fuel for cells
Water soluble lipid based energy: acetoacetic acid and b-hyrdroxybutyric acid.

Primary site of formation is the liver.

Process occurs in the mitochondrial matrix.

b-hydroxy-b-methylglutaryl CoA (HMG-CoA) is intermediate in acetoacetate synthesis from acetyl-CoA.
Ketone Body Synthesis

Key Enzymes
HMG CoA Synthase & HMG CoA Lyase. Located in liver
Ketone Body Synthesis
2 acetyl-CoA molecules are condensed
to form acetoacetyl-CoA by b-ketothiolase.

Acetoacetyl-CoA is condensed with a
second acetyl-CoA to form HMG-CoA by
HMG-CoA synthase.

HMG-CoA is cleaved by HMG-CoA lyase
to yield acetoacetic acid plus acetyl-CoA.

Acetoacetic acid is reduced to d-b-hydroxy-
butyrate by b-hyrdoxybutyrate dehydrogenase
to yield hydroxybutyrate at the expense of

Acetoacetic acid spontaneously forms acetone
+ CO2.
Absence of HMG-CoA lyase results in HMG-CoA
being used for cholesterol synthesis.
Ketone Bodies
Ketone body formation can be considered an overflow pathway.

Stimulated when acetyl-CoA accumulates due to deficient carbohydrate utilization, oxaloacetate levels are low, citrate synthase activity is low and accumulation of acetyl-CoA results.

Energy is derived from beta-hyrdoxybutyrate being converted to acetoacetyl-CoA in tissues other than the liver, such as the heart and muscle. This conserves carbohydrate for metabolism by the brain.
Ketone Bodies Flow Chart
B-hydroxybutyrate to acetoacetate (NAD+ to NADH + H+)

acetoacetate to Acetoacetyl-CoA (Succinyl-CoA to Succinate)

Acetoacetate: succinyl CoA Transferase - not in liver but in peripheral tissue
Diabetic Ketoacidosis
The absence of insulin, the primary anabolic hormone, means that tissues such as muscle, fat, and liver do not take up glucose.

Counter regulatory hormones, such as glucagon, growth hormone, and catecholamines, enhance triglyceride breakdown into free fatty acids and gluconeogenesis, which is the main cause for the elevation in serum glucose in DKA.

Beta-oxidation of these free fatty acids leads to increased formation of ketone bodies.
Diabetic Ketoacidosis (cont)
Overall, metabolism in DKA shifts from the normal fed state characterized by carbohydrate metabolism to a fasting state characterized by fat metabolism.

Secondary consequences of the primary metabolic derearrangements in DKA include an ensuing metabolic acidosis as the ketone bodies produced by beta-oxidation of free fatty acids deplete extracellular and cellular acid buffers.
Diabetic Ketoacidosis (cont)
The hyperglycemia-induced osmotic diuresis depletes sodium, potassium, phosphates, and water as well as ketones and glucose.

Commonly, the total body water deficit is 10%, and the potassium deficit is 5 mEq per kg of body weight. The total body potassium deficit may be masked by the acidosis, which sustains an increased serum potassium level. The potassium level can drop precipitously once rehydration and insulin treatment start.
Regulation of Lipid Metabolism - Synthesis
Increase release of insulin

Increase protein phosphatase activity + Acetyl CoA carboxylase

Malonyl CoA
Regulation of Lipid Metabolism - Degredation
Increase release in glucagon, epinepherine

Increase protein kinase activity + hormone sensitive lipase
Most abundant phospholipid in humans
Phosphatidlcholine (lecthin)
Which phospholipids are an ether and not esters?
ethanolamine plasmalogen and platlet activating factor
Phospholipid Surfactant
Dipalmitoylphosphatidylcholine (DPCC) (dipalmitoyllecithin) (16:0) is the major component of surfactant in the lungs (80%).

It is produced by type II epithelial cells and prevents atelectasis.

Decreases surface tension of the fluid layer of the lung.

Surfactant also contains: PG, PI and 2 surfactant proteins.
Phosphatidic Acid Synthesis
2 sequences to synthesize

start with glycerol 3-phosphate

end with diacyglycerol
Phosphatidylcholine Synthesis
Start with choline from diet.

Rate limiting step is the cytidylyl transferase reaction. Binding of cytosolic
inactive enzyme, activates it. Regulated by cAMP and fatty acyl-CoA. cAMP
dependent protein kinase phosphorylation dissociates enzyme from ER membrane and makes it inactive. Dephosphorylation and rebinding activates
Phosphatidylethanolamine Synthesis
Start with Ethanolamine Phosphotransferase from liver or brain.

Repeated methylation involved
Phospholipid Remodeling: Asymmetric Phospholipids
Begin with phospholipids.
Glucocorticoids inhibit.
Phospholipase A1 to 2-Acyl-lysophosphatide

Phospholipase A2 to 1-Acyl-lysophosphatide

Phospholipase A1 and A2 can remove fatty acids selectively from either carbon 1 or carbon 2 of the glycerol backbone.
Roles of Cholesterol
Membrane structure

A precursor for the synthesis of the steroid hormones and bile acids.

Both dietary cholesterol and that synthesized de novo are transported through the circulation in lipoprotein particles. The same is true of cholesteryl esters, the form in which cholesterol is stored in cells.
Regulation of Cholesterol Synthesis
The synthesis and utilization of cholesterol must be tightly regulated in
order to prevent over-accumulation and abnormal deposition within the body.
Of particular importance clinically is the abnormal deposition of cholesterol and cholesterol-rich lipoproteins in the coronary arteries. Such deposition, eventually leading to Atherosclerosis, is the leading contributory factor in diseases of the coronary arteries.
Most plasma cholesterol is?
Most plasma cholesterol is in an esterified form, with a fatty acid attached at C-3. This makes it even more hydrophobic then free cholesterol.
Cholesterol Biosynthesis
All carbon atoms of cholesterol are derived from acetate.

Reducing power in the form of NADPH is provided mainly by glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase of the pentose phosphate pathway

The first two reactions in cholesterol biosynthesis are shared by the pathway that produces ketone bodies
RLS of Cholesterol Biosynthesis
HMG-CoA Reductase
5 Steps of Cholesterol Biosynthesis
1. Acetyl-CoAs are converted to 3-hydroxy-3-methylglutaryl-CoA

2. HMG-CoA is converted to mevalonate

3. Mevalonate is converted to the isoprene based molecule, isopentenyl pyrophosphate (IPP), with the concomitant loss of CO2

4. IPP is converted to squalene

5. Squalene is converted to cholesterol.
Cholesterol Biosynthesis Features
The acetyl-CoA utilized for cholesterol biosynthesis is derived from an
oxidation reaction (fatty acids or ketogenic amino acids) in the mitochondria and is transported to the cytoplasm by the same process for fatty acid synthesis.

All the reduction reactions of cholesterol biosynthesis use NADPH as a cofactor.

Acetyl-CoA units are converted to mevalonate by a series of reactions
that begins with the formation of HMG-CoA.

HMG-CoA is converted to mevalonate by HMG-CoA reductase. HMG-CoA reductase absolutely requires NADPH as a cofactor and two moles of NADPH are consumed during the conversion of HMG-CoA to mevalonate.
Critical Point of Cholesterol Biosynthesis
The reaction catalyzed by HMG-CoA reductase is the rate limiting step of cholesterol biosynthesis, and this enzyme is subject to complex regulatory controls
Regulation of HMG CoA Reductase
HMG CoA inactive to active

HMG-CoA reductase is most active in the dephosphorylated state.

Phosphorylation is catalyzed by AMP-activated protein kinase, AMPK

Insulin stimulates the removal of phosphates and, thereby, activates HMG-CoA
reductase activity. - IN LIVER
Drug Therapy for Dyslipidemia
Statins-competitive inhibitors of HMG-CoA Reductase.

5 large well controlled clinical trails have documented safety and efficacy for:

Reduces fatal and non-fatal coronary heart disease (CHD), strokes and total mortality.
Drug Therapy for Dyslipidemia (cont)
Statins exert their major effect-reduction of LDL levels-through a mevalonic acid-like moiety that competitively inhibits HMG-CoA reductase by product inhibition.

Statins affect blood cholesterol levels by inhibiting cholesterogenesis in the liver, which results in increased expression of the LDL receptor gene. The greater number of LDL receptors on the surface of hepatocytes results in increased removal of LDL from the blood thereby lowering LDL-C levels.
Excess LDL leads to cholesterol deposited on
Cell wall
The Utilization of Cholesterol
Cholesterol is transported in the plasma predominantly as cholesteryl esters associated with lipoproteins.

Dietary cholesterol is transported from the small intestine to the liver within chylomicrons. Cholesterol synthesized by the liver, as well as any dietary cholesterol in the liver that exceeds hepatic needs, is transported in the serum within LDLs.

The liver synthesizes VLDLs and these are converted to LDLs through the action of endothelial cell-associated lipoprotein lipase.
The Utilization of Cholesterol (cont)
Cholesterol found in plasma membranes can be extracted by HDLs and esterified by the HDL-associated enzyme LCAT.

The cholesterol acquired from peripheral tissues by HDLs can then be transferred to VLDLs and LDLs via the action of cholesteryl ester transfer protein (apo-D) which is associated with HDLs.

Reverse cholesterol transport allows peripheral cholesterol to be returned to the liver in HDLs.

Ultimately, cholesterol is excreted in the bile as free cholesterol or as bile salts following conversion to bile acids in the liver.
Bile Acids - general
The most abundant bile acids in human bile are chenodeoxycholic acid (45%) and cholic acid (31%).

These are referred to as the primary bile acids.

Within the intestines the primary bile acids are acted upon by bacteria and converted to the secondary bile acids, identified as deoxycholate (from cholate) and lithocholate (from chenodeoxycholate).

In liver the carboxyl group of primary and secondary bile acids is conjugated via an amide bond to either glycine or taurine before their being resecreted into the bile canaliculi. These conjugation reactions yield glycoconjugates and tauroconjugates, respectively.
Clinical Significance of Bile Acid Synthesis - 4 physiologically significant functions
1. their synthesis and subsequent excretion in the feces represent the only significant mechanism for the elimination of excess cholesterol.

2. bile acids and phospholipids solubilize cholesterol in the bile, thereby preventing the precipitation of cholesterol in the gallbladder.

3. they facilitate the digestion of dietary triacylglycerols by acting as emulsifying agents that render fats accessible to pancreatic lipases.

4. they facilitate the intestinal absorption of fat-soluble vitamins.
Sphingolipids - General
Sphingolipids are a component of all membranes but are particularly abundant in the myelin sheath.

Sphingomyelins are sphingolipids that are also phospholipids.

Sphingomyelins are important structural lipid components of nerve cell membranes.

The predominant sphingomyelins contain palmitic or stearic acid N-acylated at carbon 2 of sphingosine.
Ptotective Sphingolipid Structural Features
The sphingolipids, like the phospholipids, are composed of a polar head group and two nonpolar tails.

The core of sphingolipids is the long-chain amino alcohol, sphingosine. Amino acylation, with a long chain fatty acid, at carbon 2 of sphingosine yields a ceramide.
Sphingomyelin Synthesis
Sphingolipids include the sphingomyelins and glycosphingolipids
(the cerebrosides, sulfatides, globosides and gangliosides).

Sphingomyelins are sphingolipids that are also phospholipids.

The sphingomyelins are synthesized by the transfer of phosphorylcholine
from phosphatidylcholine to a ceramide in a reaction catalyzed by
sphingomyelin synthase.
Endproducts of Sphingomyelin Synthesis
Sphingomyelin and Diacylglycerol
Degredation of Sphingomyelin
Sphingomyelin is degraded by sphingomyelinase, a lysosomal enzyme
that hydrolytically removes phosphorylcholine, leaving a ceramide.
Sphingomyelin Degredation Diseases
All are rare storage diseases

Gaucher's Disease - easiest to treat with ceramide enzyme

Krabbe Disease

Niemann-Pick Disease
Disease States Resulting from Defective Spingomyelinase
Defects in the enzyme acid sphingomyelinase result in the lysosomal storage disease known as Niemann-Pick disease.

In Niemann-Pick disease, lipid, mainly sphingomyelin,
accumulates in reticuloendothelial and other cell types
throughout the body.

The accumulation in ganglion cells of the central nervous
system leads to cell death.
Disease States Resulting from Defective Spingomyelinase

Hepatosplenomegaly, retarded physical and mental growth
and severe neurologic disturbances are features.

Symptoms usually develop by 6 months and death occurs by 3 years of age.

There are at least 4 related disorders identified as Niemann-Pick
disease Type A and B (both of which result from defects in acid
sphingomyelinase), Type C1 and a related C2 and Type D. Types
C1, C2 and D do not result from defects in acid sphingomyelinase
Have ceramide backbones

Glycosphingolipids, or glycolipids, are composed of a ceramide backbone with a wide variety of carbohydrate groups (mono- or oligosaccharides) attached to carbon 1 of sphingosine.

The four principal classes of glycosphingolipids are the cerebrosides, sulfatides, globosides and gangliosides.
Cerebrosides have a single sugar group linked to ceramide. The most common of these is galactose (galactocerebrosides), with a minor level of glucose (glucocerebrosides).

Galactocerebrosides are found predominantly in neuronal cell membranes. By contrast gluco-cerebrosides are not normally found in membranes, especially neuronal membranes; instead, they represent intermediates in the synthesis or degradation of more complex glycosphingolipids.
Glycolipid Synthesis
Galactocerebrosides are synthesized from ceramide and UDP-galactose
Glucocerebrosides are synthesized from ceramine and UDP-glucose.
Globosides and Gangliosides
Globosides represent cerebrosides that contain additional
carbohydrates, predominantly galactose, glucose or GalNAc. Lactosyl
ceramide is a globoside found in erythrocyte plasma membranes.
Ceramide trihexoside contains glucose and two moles of galactose and
accumulates, primarily in the kidneys, of patients suffering from Fabry's
Globosides and Gangliosides disorders
Fabry disease is characterized by
accumulation of globosides, a
reddish-purple skin rash, kidney and heart
failure, and burning pain in the lower

Gaucher’s disease is characterized
by accumulation of glucocerebroside,
liver and spleen enlargement, erosion
of long bones and pelvis and mental
retardation in infantile form only.
Gangliosides are very similar to globosides except that they also contain NANA in varying amounts.

CNS is unique in that more than 50% of the sialic acid is in

NANA is N-acetylneuraminic acid or sialic acid.

The linkage of NANA always involves the OH group on the number 2 carbon of the carbohydrate.
Common Gangliosides
The specific names for gangliosides are a key to their structure. The letter G refers to ganglioside,and the subscripts M, D, T and Q indicate that the molecule contains mono-,di-, tri and quatra(tetra)-sialic acid. The numerical subscripts 1, 2 and 3 refer to the carbohydrate sequence that is attached to ceramide; 1 stands for GalGalNAcGalGlc-ceramide, 2 for GalNAcGalGlc-ceramide and 3 forGalGlc-ceramide.
Choleratoxin binds to GM1on
intestinal mucosal cells allowing
the A subunit cell entry where it
ADP ribosylates G subunit of adenylate cyclase and activates it
Prostaglandins (PGs)
Thromboxanes (TXs)
Leukotrienes (LTs).
Prostaglandins (PGs)
Thromboxanes (TXs)
Leukotrienes (LTs).
The PGs and TXs are collectively identified as prostanoids.
Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names.
Effects of Eicosanoids
The eicosanoids produce a wide range of biological effects on inflammatory responses (predominantly those of the joints, skin and eyes), on the intensity and duration of pain and fever, and on reproductive function (including the induction of labor). They also play important roles in inhibiting gastric acid secretion, regulating blood pressure through vasodilation or constriction, and inhibiting or activating platelet aggregation and thrombosis.
Prostaglandin, Leukotriene, and Thromboxane begin with
Atachidonic Acid

Easiest to stop cascade at NSAID, COX-1, COX-2
Cause constriction or dilatation in vascular smooth muscle cells

Cause aggregation or declumping of platelets
sensitize spinal neurons to pain

constrict smooth muscle

Regulate inflammatory mediation

regulate calcium movement

regulate hormone

regulation control cell growth
Mediators of allergic response



Increased vascular permeability

Mobilized intracellular calcium

Promotes platelet aggregation

Contraction of smooth muscle
Classes of Prostaglandins
Three major classes of prostaglandins: A, E, F
Classes are distinguished from the functional groups on the cyclopentane ring.
Series with classes of Prostaglandins
E series contains b-hydroxy-ketone ring

F series contains 1,3 diols

A series contains a,b-unsaturated ketones

Numbers denote the number of unsaturated bonds in the side chains.
Arachidonate Synthesis Begins With
Synthesis of E and F Prostaglandins from FA precursors - Major Pathways
PGE1 - Eicosatrienoic Acid - greatest amt in human body

PGE2 - Arachidonic Acid
Synthesis of E and F Prostaglandins from FA precursors - Minor Pathway
Derived from Linolenic Acid

PGE3 - Eicosapentaenoic Acid
Prostaglandin Synthesis
Synthesis of the clinically relevant prostaglandins and thromboxanes from
arachidonic acid. Numerous stimuli (e.g. epinephrine, thrombin and bradykinin) activate phospholipase A2 which hydrolyzes arachidonic acid from membrane phospholipids. The prostaglandins are identified as PG and the thromboxanes as TX. Prostaglandin PGI2 is also known as prostacyclin.

KNOW CHART - Lec30 Pg 9
Prostaglandins and Throboxanes Synthesis
The pathway is initiated through the action of prostaglandin G/H synthase, PGS. This enzyme possesses two activities, cyclooxygenase (COX) and peroxidase.

There are 2 forms of the COX activity. COX-1 (PGS-1) is expressed constitutively in gastric mucosa, kidney, platelets, and vascular endothelial cells.
Prostaglandins and Throboxanes Synthesis (cont)
COX-2 (PGS-2) is inducible and is expressed in macrophages and monocytes in response to inflammation. T

the primary trigger for COX-2 induction in monocytes and macrophages is platelet-activating factor, PAF and interleukin-1, IL-1.

Both COX-1 and COX-2 catalyze the 2-step conversion of arachidonic acid to PGG2 and then to PGH2.
Leukotriene Synthesis
Synthesis of the clinically relevant leukotrienes from arachidonic acid.

Numerous stimuli (e.g. epinephrine, thrombin and bradykinin) activate phospholipase A2 which
hydrolyzes arachidonic acid from membrane phospholipids. The 1st step for synthesis of leukotrienes(LTs) is catalyzed by Lipoxygenase.
5-Lipoxygenase, in leukocytes, catalyzes arachidonate  5-HPETE
(5-hydroperoxy-eicosatetraenoic acid). 5-HPETE is then converted to various
leukotrienes that induce inflammation and asthmatic constriction of the bronchioles.

LTA4 is unstable intermediate
Mechanism of Action of Non-Steroidal Anti-Inflammatory Drugs
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as ibuprofen, indomethacin, naproxen, phenylbutazone and aspirin, all act upon the cyclooxygenase activity, inhibiting both COX-1 and COX-2.

Because inhibition of COX-1 activity in the gut is associated with NSAID-induced ulcerations, pharmaceutical companies have developed drugs targeted exclusively against the inducible COX-2 activity (e.g. celecoxib and rofecoxib).
Mechanism of Action of Non-Steroidal Anti-Inflammatory Drugs (cont)
Another class, the corticosteroidal drugs, act to inhibit phospholipase A2, thereby inhibiting the release of arachidonate from membrane phospholipids and the subsequent synthesis of eicosinoids.
Amino Acid Metabolism
Amino acids undergo transamination and oxidative deamination. The ammonia released by this process is transported in the form of glutamine or alanine. Ammonia gets detoxified to urea in the liver during the urea cycle. Amino acids are degraded into various compounds. They are synthesized from different intermediates of the citric acid cycle.

AA not stored in body like fats.
Amino Acid Pool
-Dietary Protein
-Synthesis of body protein
-Synthesis of non-protein Nitrogen containing cmpds
-Conversion of AA to glucose to glycogen, FA, CO2
-De novo synthesis of nonessentail aa
-Degredation of body proteins
Nonessential AA
ody can supply/make them

Essential AA
Only from diet

Why are Arginine, Methionine, & Phenylalanine essential?
because the body does not
have the synthetic capacity to meet the demands.
What are methionine and phenylalanine used to produce?
Methionine is used to
produce cysteine.

Phenylalanine is used to produce tyrosine.
Metabolic fate of nonessential aa and histidine
Points of entry at various steps of the TCA cycle, glycolysis, and gluconeogenesis
Metabolic fate of essential aa plus cysteine and tyrosine
Carbons from amino acids enter
intermediary metabolism at seven
points in the glycolytic pathway
and the TCA cycle.
The seven products of amino acid catabolism
Succinyl CoA
Acetyl CoA
Amino acid deamination

3 Types
The first step in catabolism of most AA is the transfer of their a-amino group to a-ketoglutarate. The products are an a-keto acid and glutamate.

All amino acids, with the exception of lysine and threonine, participate in transamination.

A transaminase or an aminotransferase is an enzyme that catalyzes a type of reaction between an amino acid and an α-keto acid.
Glutamate-pyruvate aminotransferase reaction
alanin & transaminase
Present in many tissues
Glutamate-oxaloacetate transaminase:
facilitates the conversion of aspartate
and alpha-ketoglutaric acid to oxaloacetate and glutamate.
A transamination between alanine and aspartate must occur via coupled reaction.
Mechanism of action of aminotransferase
All aminotransferases require the coenzyme
pyridoxal phosphate. Aminotransferases
act by transferring the amino group of an amino
acid to the pyridoxal part of the coenzyme
to generate pyridoxamine phosphate.

Pyridoxal phosphate is the active form of
Vitamin B6
Transamination: Two functions
Occurs during degradation/catabolism of amino acids

These reactions can also be used to synthesize amino acids needed or not present in the diet. Nonessential AA are synthesized from available "root" ketoacids (with a synthetic connection to the final amino acid) by transfer of a preexisting amino group from another AA
Disposal of Amino Acids
Urea Cycle

Transamination reactions transfer amino groups, oxidative deamination by glutamate
dehydrogenase results in the liberation of an amino group as free ammonia. The
products, a-keto acid can enter the central pathway of energy metabolism and
ammonia can enter the urea cycle.
Step One of AA Disposal

NH2 of alpha aa to a-keto acid
Step Two of AA Disposal
Oxidative Deamination (Glutamate dehydrogenase) This is a critical enzyme. This step may be reversed
Synthesis of AA
Reductive Amination (glutamate dehydrogenase) to Transamination (aminotransferase)

The reaction can be used to synthesize amino acids from the corresponding alpha
-keto acids. The direction of the reaction depends on the relative concentrations
of glutamate, alpha ketoglutarate, and ammonia and the ratio of oxidized to
reduced coenzymes (NAD+ OR NADP+).
Glutamate dehydrogenase:
In liver, oxidative deamination by glutamate dehydrogenase results in the liberation of free ammonia

The sequential action of transamination and the oxidative deamination of glutamate provide a pathway whereby the amino groups of most AA can be released as ammonia.
Glutamate Dehydrogenase in Liver
In liver, ammonia is incorporated into glutamate by glutamate dehydrogenase, which
also catalyzes the reverse reaction. Glutamate always serves as one of the amino acids
in transaminations and is thus the “gateway” between amino groups of most amino
acids and free ammonia.

Is reversible
Nitrogen cycle
Bacteria Plants to

Animal diets, proteins, aa + NH3 to

Human proteins
Transport of Ammonia
Transport of ammonia to the liver is mostly in the form of glutamine or alanine

Glutamine synthetase is responsible for the synthesis of glutamine from glutamate and NH3
Glutamate synthesis
Glutamate is synthesized by the reductive amination of a-ketoglutarate catalyzed by glutamate dehydrogenase.

In addition, glutamate arises by aminotransferase reactions, with the amino nitrogen being donated by a number of different amino acids. Thus, glutamate is a general collector of amino nitrogen.
Glutamine Biosynthesis
Glutamine is produced from glutamate by the direct incorporation of ammonia; and this can be considered a nitrogen fixing reaction.
Glutamine Synthetase Reaction
Role of glutamine is to carry ammonia from peripheral tissues to the liver where it is converted to ammonia by

glutamine + H2O -------> glutamate + NH3
Form of transport of Ammonia
Transport of ammonia is mostly in the form of glutamine or alanine

Glutamine synthetase is responsible for the synthesis of glutamine from glutamate and NH3
Glutaminase converts glutamine to glutamate and ammonia in the liver by the mitochondria excreted as urea.
Ammonia and blood
Free ammonia is toxic in the blood
Transport of ammonia
Second mechanism of transport involves alanine

Pyruvate is transaminated to form alanine (alanine-aminotransferase aka: glutamate-pyruvate transaminase).

Alanine is transported by the blood to the liver where it is converted back to pyruvate.
Urea Cycle - atoms
Occurs in Liver

N from amino in asoartate
C from bicarbonate
N from ammonia
RXNS in Urea Cycle
There are 5 enzymes. 2 in mitochondria and 3 in cytosol
Urea Cycle start and end
Starts with Carbamoyl Phosphate Synthase I (CPSI) in the mitochondria

Ends with fumarate
Allosteric Activators in Urea Cycle
Arginine is an allosteric activator and a co-factor

N-Acetylglutamate is an allosteric activator of CPS-1
1st RXN in the Urea Cycle
OTC - Orinithine Transcarbomoylase

Formation of citrulline

Ornthine is not in cellular proteins
Number of ATP's used in Urea Cycle
Intermediate precursor of urea
What in the Urea cycle for to the Citric Acid Cycle?
Cleavage of Arginiosuccinate
Argininosuccinate lyase cleaves and leaves fumarate
Oxaloacetate Fates
Transamination to aspartate

Conversion into glucose by the gluconeogenic pathway

Condensation with acetyl CoA to form citrate

Conversion to pyruvate
Cleavage of Arginine in Urea Cycle
to ornithine and urea
Key Points to AA degredation
1) Amino group of amino acids are transferred to alpha-ketoglutarate, forming an alpha-keto acid and glutamate via transaminase

2) Glutamate is deaminated to form ammonia and to regenerate alpha-ketoglutarate via glutamine dehydrogenase

3) Conversion and elimination of ammonia as urea via carbamoyl phosphate synthetase and the urea cycle enzymes

4) Metabolism of the carbon backbone (happens via TCA cycle)
Glucogenic vs. Ketogenic
Leu, Lys are degraded to acetyl CoA

Glucogenic and ketogenic: Ile, Phe, Tyr, Trp

Glucogenic: all others
Metabolic breakdown of individual amino acids
The 7 products of amino acid catabolism are:

Succinyl CoA
Acetyl CoA
One-carbon metabolism
Tetrahydrofolate (THF)

S-adenosylmethionine (AdoMet)

The role of tetrahydrofolate in amino acid metabolism
The reduced form of folic acid
A one carbon carrier that facilitate interconversion of

Methenyl: CH=
Formyl: -CHO
Formimino : CHNH
Methylene: CH2-
Methyl: CH3
N5 is the site of attachment of methyl groups

N10 is the site for formyl (HC=O) and formino-methylene (C=NH2) and

methylene ( CH2 ) and methenyl (=CH ) groups to form bridges between N5 and N10.
Interconversion of H4Folate and Roles
in Amino Acid
Starts with Methionine Salvage

Ends with Tryptophan metabolism
Biosynthesis of S-Adenosyl Methionine (SAM)
AKA Adomet
Can be activated or transferred
All of PO4 are lost
S-Adenosyl Methionine

SAM serves as a precursor for numerous methyl transfer reactions.

Methyl group transfer from AdoMet to a methyl acceptor is irreversible.

When cells need to resynthesize methionine, homocysteine methyltransferase catalyzes the transfer. (THF cofactor)
Synthesis of Serine
Two Pthwys

3-phosphoglycerate as a precursor

Derivative of Serine
Decarboxylated Serine

Tri-methylated ethanolamine


Synthesis of Tyrosine
From phenylalanine

will go to protein or produce tyrosine

phenylalanine hydroxylase is irreversible
Missing or deficient phenylalanine hydroxylase leads to the genetic disease known as phenlyketonuria (PKU), which if untreated leads to severe mental retardation.

If the problem is diagnosed early, the addition of tyrosine and restriction of phenylalanine from the diet can minimize the extent of mental retardation.
AA Metabolism Disorder:

Defective Process: Melanin synthesis from tyrosine

Defective Enzyme: Tyrosinase

Symptoms & Effects: Lack of Pigmentation. White hair, pink skin
AA Metabolism Disorder:

Defective Process: Tyrosine degradation

Defective Enzyme: Homogentisate Dioxygenase

Symptoms & Effects:Dark pigment in urine. Late developing arthritis
AA Metabolism Disorder:

Defective Process: Conversion of phenylalanine to tyrosine

Defective Enzyme: Phenylalanine hydroxylase

Symptoms & Effects: Neonatal vomitting and mental retardation
Synthesis of Methionine and Cysteine
Methionine to homocysteine via methionine synthase is irreversible

Cystathionine is final product
Tryptophan as a precursor
Niacin- a precursor for NAD and NADP

Serotonin- a neurotransmitter
Tyrosine as a precursor
Thyroid hormones T3 and T4

Catacholamines Dopamine, Norepinephrine, Epinephrine

Melanin- a pigment of skin, hair, and eye
Glycine as a precursor
Creatine-used as high energy compound, phosphocreatine

Glutathione- tripeptide, gamma glutamyl cysteinyl glycine,
reducing agent, helps remove toxic peroxides

Heme-iron containing prosthetic group
Glutamine as a precursor
GABA_ g-aminobutyric acid, an inhibitory neurotransmitor
Tyrosine and Catecholamine Synthesis
Tyrosine to
Dopamine to
NE to
Synthesis of 5-HT and Tryptophan
Start at tryptophan and end with 5-HT and Melatonin
Transamination of a-keto acids
ie: pyruvate+glutamate alanine+ a-ketoglutarate
ie: oxaloacetate +glutamate aspartate +
aspartate asparagine
Synthesis of other aa
phenylalanine tyrosine
Synthesis FROM other aa
Serine glycine

phenylalanin tyrosine

methionine cysteine

glutamate glutamine
What are purines and pyrimidines?
Purines and pyrimidines, often called bases, are
nitrogen-containing heterocyclic compounds with these structures.
This is the structure of a basic purine molecule. Notice the numbers on the rings. There are two ring structures.

Purine bases you will find in DNA are Adenine and Guanine
Pyrimidines have a single six sided ring structure.

Thymine, cytosine, uracil

Uracil is found in RNA
Naming nucleotides and nucleosides
The purine NSs  end in "-sine" :   adenosine and guanosine

The pyrimidine NSs end in "-dine" : cytidine, uridine, deoxythymidine

To name the NTs, use the NS name, followed by "mono-", "di-" or "triphosphate":   adenosine monophosphate, guanosine triphosphate, deoxythymidine monophosphate
Functions of Nucleotides
Energy metabolism
Monomeric units of nucleic acids
Physiological mediators
Precursor function
Components of coenzymes
Coenzyme A, FAD, NAD+, NADP+
Activated intermediates
SAM (AdoMet), CDP-choline (phospholipids)

Allosteric effectors
Metabolism of Purine Nucleotides
Synthesis of purine nucleotides
Purine salvage
Purine nucleotide interconversions
GTP and tetrahydobiopterin
Uric acid
Purine Synthesis
PRPP (5-phosphoribosyl-1-pyrophosphate) to PRA (5-phosphoribosylamine via N from glutamine is the commitment step
Synthesis of purines requires
Amino acids
Glutamine (2)


One carbon units transferred via THF (2)
Atoms om the purine ring
See Lecture 35, Pg 10
Regulation of Purine Synthesis
Is self regulating

Regulated by IMP, GMP, AMP
Purine Feedback System
If increase in AMOP, then negative effect on pthwy

GOUT if overproduction of IMP

This is the commitment step

Rate of AMP production increases with increasing concentrations of GMP; rate of GMP production increases with increasing concentrations of AMP
Purine Salvage Transferases
Adenine phophoribosyl transferase (APRTase) &

Hypoxanthine-guanine phosphoribosyl transferase (HGPRTase)
Salvage of purine nucleobases via phosphoriboseyl transferases are
RXNS regulated by end product
Interconversions of purine nucleotides
Amount of GDP, GTP, etc has an effect on all other compounds
Synthesized from GTP

Co-factor in many RXNS
Metabolism of purine nucleotides lead to
Uric Acid as its final product
Too much uric acid equals
Gout is a disorder characterized by high levels of uric acid in blood, as a result of either the overproduction or under excretion of uric acid.

Gout is treated with
drugs such as allopurinol
that inhibit

Suicide inhibitors bind with xanthineoxidase
Synthesis of pyrimidine nucleotides
Carbamoyl phosphate synthase II is regulated step (carbamoyl phosphate and aspartate)

Committed step is carbamoylasparate
Urea Cycle
Pyrimidine Synthesis
g-amide group of glutamine
Source of atoms for pyrimidines
N - glutamine amide
C- HCO3-
Rest of ring - Aspartate
Synthesis of pyrimidines vs. purines.
First, the ring structure is assembled as a free base in pyrimidines, not built upon PRPP like purines.

Second, there is no branch in the pyrimidine synthesis pathway.
Synthesis of CTP from UTP
CTP Synthetase takes Uridine 5-triphosphate to Cytidine 5-triphosphate
In De novo synthesis, the pyrimidine ring is
synthesized from bicarbonate, aspartate, and glutamine (or ammonium ion)
Deoxyribonucleotide formation
Deoxyribonucleotides are formed by the reduction of ribonucleoside diphosphates.

All deoxyribonucleotides are synthesized from ribonucleotides by the enzyme ribonucleotide reductase.

The enzyme is highly regulated.
Deoxyribonucleotide formation enzyme
ribonucleotide reductase

Ribonucleoside diphosphate to deoxyribonucleoside diphosphate
Role of ribonucleotide reductase in DNA synthesis
1-5 are kinase

5 is DNA polymerase
Synthesis of deoxythymidine nucleotide
Once Carbon Donor
Thymidylate Synthase

Deoxthymidylate (dTMP) is
formed by methylation
of deoxyuridine 5’-mono
Phosphate (dUMP)
Deoxyribopyrimidine interconversions of pyrimidine nucleotides
Deoxyuridine to dUMP or

Deoxyctidine to dCMP to dUMP
Key Point for deoxypyrimidine nucleotide synthesis
UMP is the precursor for all the pyrimidine nucleotides
Pyrimidine nucleotides are degraded to
b-amino acids
Pathways to degrade the pyrimidine nucleotides of DNA and RNA
RNA and DNA to Uracil

DNA to Thymine
Degredation of Uracil and Thymine
Uracil to b-alanine

Thymine to b-aminoisobutyrate
Nucleoside and Nucleotide Kinases
Nucleotide mono-, di-, and triphosphates are interconvertible
For example - UMP → UDP → UTP

• Specific nucleoside (X) monophosphate kinases make nucleoside


• A nucleoside diphosphate kinase, with broad substrate specificity,
interconverts dinucleosides and trinucleosides (this enzyme uses
both ribo- and deoxynucleosides as substrates.

Nucleotide function in coenzyme synthesis
NAD in Nucleotide function in coenzyme synthesis
start at nicotinamide and end at NAD (nicotinamide adenine dinucleotide)
FAD as function in nucleotide coenzyme synthesis
start at riboflavin

end at FAD (flavin adenine dinucleotide)
CoA as function in nucleotide coenzyme synthesis
start at pantothenate

and at CoA

PRPP is the KEY molecule in:

de novo synthesis of purine and pyrimidine nucleotides

salvage of purine and pyrimidine bases

and synthesis of NAD+.
Synthesis of PRPP
Ribose 5-phosphate to PRPP via PRPP synthstase Mg2+
Some Drugs
dUMP can be converted to dTMP using thymidylate synthase -an enzyme targeted by anticancer drugs such as 5-flurouracil.

The regeneration of THF from DHF produced in the thymidylate synthase reaction requires dihydrofolate reductase -an enzyme targeted by the drug, methotrexate.
Non-competitive antagonist

Suicide inhibitor

Acts at thymidylate synthase
3 classic anti-cancer drugs
Purine Analog

Pyrimidine Analog

Pyrimidine Analog
Folic Acid Antagonist
Acyclovir, AZT, pyrimidine
Acyclovir a purine analog, and AZT a pyrimidine analog are used in the treatment of HSV and HIV infections