Touro Biochem

Presence of myoglobin in urine indicating destruction of skeletal or heart muscle

Histidine
Isoleucine
Leucine
Lysine
Methionine
Phenylalanine
Threonine
Tryphtophan
Valine

amino acid sequence
8 a helices
3-D spherical shape with binding pocket for heme

2 aB dimers (similar in structure to Mb) that form quarternary structure

4 hemes that can bind 4 O2 molecules

resides in plasma membrane of intestinal cells

digests proteins from amino end and makes di and tri peptides which are released into the blood to go to other tissues.

Deficient amounts of a chain subunits. y or B chains form homodimers (HbBarts yyyy and HbH BBBB respectively)

These homodimers bind O2 super tight and it doesn't get released into tissues.

Deficient amounts of B chains.

y chains are increased (HbF)

a chains precipitate which cause issues with RBC formation.

HbS

decreased oxyhemoglobin

increased methemoblobin (hemoglobin with Fe3+)

YYYY--Bart's
BBBB--HbH
BBBBBBBBBB--Bchain precipitate

aaaa--alpha precipitate which inhibits RBC formation
ayay--HbF

The Beta chain precipitates don't form or are not as detrimental as the a chain precipitates in B-Thalassemia

Product Inhibition

Allosteric regulation

Covalent modification through phosing / dephos

Proteolytic processing

Regulation of enzyme levels

The product of the enzymatic reaction is the inhibitor or the enzyme.

Think negative feedback. Heme is the inhibitor to the enzyme that catalyzes the synthesis of heme

heme also downregulates transcription of the gene that makes that rate limiting enzyme

Heme itself is the inhibitor for the enzyme d-aminolevulinic acid. d-aminolevulinic acid is the enzyme for the rate limiting reaction that starts the production for heme.

The presence of heme also downregulates the transcription of the gene for d-aminolevulinic acid therefore also decreasing the expression of the enzyme in the first place.

Heme itself is the inhibitor for the enzyme d-aminolevulinic acid. d-aminolevulinic acid is the enzyme for the rate limiting reaction that starts the production for heme.

The presence of heme also downregulates the transcription of the gene for d-aminolevulinic acid therefore also decreasing the expression of the enzyme in the first place.

allosteric regulation is when a regulator binds to the enzyme in a place other than the active site of that enzyme.
The regulator can either enhance or diminish the activity of the enzyme.

O2 is a homotropic allosteric regulator for Hb. This means it is the substrate and regulator (binding of O2 changes Hb to bind subsequent O2 easier)

a hetertropic allosteric regulator is a regulator that is NOT the substrate for the enzyme.

CO2, H+ and 2,3-BPG are all hetertropic allosteric regulators for Hb.

kinases phosphorylate enzymes and phosphatases dephosphorylate enzymes. This can have either a positive or negative regulation depending on the enzyme.

protein phosphotase dephos's glycogen phosphorylase and decreases the conversion of glycogen to glucose 1-Phosphate.
Increased breakdown of glycogen occurs when phosphorylase kinase phos's glycogen phosphorylase.

So when glycogen phosphorylase gets phos'd=activated.
dephos'd=deactivated

protein kinase A phos's glycogen synthase which prompts it to make less glycogen

Protein phosphotase dephos's glycogen synthase and it activates the enzyme to make more glycogen

example of phosphorylation and dephosphorylation as a means of enzymatic regulation.

This relates to enzymes you only want to be active in certain environments. An inactive enzyme (proenzyme) gets cleaved and then becomes active.

trypsinogen. digestive enzymes produced in the pancrease that you don't want to start working until they are in the intestine

proteolytic processing.

proenzymes are only cleaved when there is a need so that your blood can flow normally under normal conditions.

Enzyme levels refer to actual number of enzymes produced or in the system. This relates to transcription, translation and degradation of enzyme.

heme is the inhibitor or regulator of the expression of the gene for d-aminolevulinic acid which is the starting enzyme to make heme. So if there is a lot of heme in your system less of this gene is going to be expressed.

irreversible means the inhibitor binds to its enzyme (covalent or not) really strongly without letting go. This a noncompetitive for graph purposes, because if it never lets go there is no competition. Cannot be overcome with the addition of extra substrate.

an example is sarin gas or aspirin.

a reversible inhibitor is one that does not bind too tightly to its enzyme. Has 2 subgroups: competitive and non-competitve

examples of competitive, reversible inhibition is statins, Cox inhibitors and BP meds (captopril)

non-competitve reversible inhibitors bind to ES complex or just to E, but don't decrease ES formation, just decrease product formation.

Vmax unchanged
enzyme has lower affinity for substrate so Km is increased (moves closer to x axis)

liver

Km remains the same
Vmax is decreased (line moves higher on y axis and is thus smaller)

a-amino group transferred to an a-ketoglutarate (aminotransferase) to make glutamate and then it is oxidatively deaminated (glutamate dehydrogenase) to free NH4+

works like an irreversible inhibitor only once the inhibitor binds with the enzyme, it gets changed so that it cannot get free

Asp aminotransferase
Asp + aKG<-->OAA + Glu

Ala aminotransferase
Ala + aKG<--> pyruvate + Glu

Irreversible inhibitor is stuck, but unchanged and a suicide inhibitor is changed and really stuck

oxidative deamination

dehydrogenation of C-N bond and hydrolysis of Schiff base

Can use NAD+ or NADP+

suicide inhibitor

binds to xanthine oxidase so the enzyme cannot catalyze the production of uric acid from hypoxanthine xanthine

suicide inhibitor.

Binds to transpeptidase so peptidyglycans cannot cross link

It is an irreversible inhibitor

binds to acetylcholinesterase and thus prevents the breakdown of acetylcholine and messes with muscles.

competitive, irreversible inhibitor

Binds to COX and prevents arachidonic acid from turning into a prostaglandin=pain relief

captopril is a BP lowering med
competitive inhibitor of ACE so angiotensin I doesn't get converted the vaso constricting angiotensin II

competitve reversible inhibition of HMG-CoA reductase to prevent de novo syn of cholesterol

Transported to the liver as pyruvate (Ala cycle puts nitrogen on pyruvate to get Ala which goes in blood to liver to be made back into pyruvate again when liver deaminates it)

Glutamine synthetase makes glutamine from glutamate then it's sent to liver to be deaminated there into urea.

"aspartate aminotransferase"

Liver disease

alanine aminotransferase

acute liver tissue damage
over 35 IU/L is abnormal

One N is from Asp and the other is from free NH4+

Carbon is from HCO3-

amylase and lipase

biliary obstruction (gallstones)

mitochondrial matrix

GGT's are a sign of severe liver disease like hepatitis or cirrhosis

carbamoyl phosphate synthetase (CPS)

Abdi probably had elevated alkaline phosphatase enzymes in his Dx.

acid phosphotase

2 ATP

N-acetylglutamate

CK

Carbamoyl Phosphate Synthetase

look for both elevated GGT and LDH.

ornithine uses ornithine transcarbamolyase to turn into citrulline in the mitochondrial matrix.

Citrulline condenses with aspartate in the cytoplasm

CK levels return to normal after 48-72 hours, so if someone had a mild infarct earlier in the week this test wouldn't catch it.

enzyme that facilitates C bonding with O, S, N via ATP hydrolysis

argininosuccinate synthetase is the enzyme that catalyzes the reaction from citrulline to argininosuccinate in the cytoplasm.

Needs ATP

cleaver of CC, CO, CS and CN bonds

enzyme that facilitates ox-reduction reactions (NAD+ to NADH rx)

enzyme that facilitatesC, N or P transfer
Transfering to THF

enzyme that facilitates cleavage of bonds by adding water

enzyme that facilitates racemization

4 ATP

2 or more different enzymes that have a similar function but that operate in different tissues.

hexokinase / glucokinase (hexo is in tissues / gluco is in liver for first step of breakdown of glucose)
lactate dehydrogenase
creatine kinase

fumarate

fumarate-->malate-->OAA

These guys are inactive that have an extra protein sequence that once it gets cleaved, the enzyme becomes active.

digestive enzymes and blood cascase enzymes

apo is inactive and once it's matching cofactor comes along it becomes the activated holoenzyme

Digestive GI

Blood coag plasma

matrix remodelers

Leu, Lys

acetylcholinesterase, modulates ACh levels extracellularly

COX's can activate prostaglandins intracellularly

Ile, Phe, Trp, Tyr, Thr

Ala + aKG ----> pyruvate + Glu

Asp aminotransferase

Asp + aKG---> OAA+ Glu

Asn ----> NH4+ + Asp
via asparaginase

In two ways, it either becomes transaminated to OAA
or
becomes fumarate in Urea Cycle

glutamate is oxidatively deanimated to a-ketoglutarate by the enzyme glutamate dehydrogenase

Oh god.

Penance

please

isn't it?

Phe hydroxylase

electron carrier (deriviative of cofactor biopterin)

Cofactor for breaking down Phenylalanine (PKU)
Tyrosine (decreased catecholimines=neuro probs)
Tryptophan (no seratonin or melotonin=pellegra)

p-hydroxyphenylphyruvate

Because. That is the only reason.

...squared.

lack of Phe hydroxylase

20% increase in Phe in blood and body fluids

causes severe mental retardation if left untreated

decreased brain weight and defective myelination causes unknown.

low Phe diet is only treatment beginning before age 1

HILL Make Personal Training Take Valor

Histidine
Isoleucine
Leucine
Lysine
Methionine
Phenylalanine
Threonine
Tryptophan
Valine

acetoacetate

3-hydroxybutyrate

ketogenic AA are broken down to acetoacetate and acetyl-CoA in liver.

ketoacidosis is a result of insulin not working, cells can't take up glucose for energy so the body breaks down triglycerides for fuel and releases these ketone bodies in excess.

L's follow k

Leucine
Lysine

Take a TTTIP from me (Sublime is Phun...)

threonine
tryptophan
Tyrosine
Isoleucine
Phenylalanine

3 G's 4A's V(five)CHMPS

Alanine
Arginine
Aspartate
Asparagine

Glutamate
Glutamine
Glycine

Valine
Cysteine
Histidine
Methionine
Proline
Serine

They are stored in glycogen or triglycerides

Energy production

glycolysis

glycolysis
Gly
Ser
Ala
Cys

Oxaloacetate
Asparagine
Aspartate

a-Ketoglutarate
Glutamate
Glutamine
Pro
Arg

Phenylalanine
Tyrosine

PLP (B6) (pyrodoxialphosphate)

Tetrahydropholate (THF)

B12

BH4 (Tetrahydrobioptirin)

Thiamine pyrophosphate (B1) and lipoate

Asparagine---->Aspartate

Oxaloacetate is the precursor to citrullate in glycolysis.

leukemic cells depend on Asparagine to divide fast and if you use asparaginase it will use up all the Asparagine and turn it into Aspartate. There is no Asparagine left for the tumor.

F = F

Folic acid deficiency
Decreased levels of THF thus limit histidine metabolism becasue it is a cofactor

This is due to a deficieny in histidinase but it is not clinically significant.

Glu
Glutamate
Histidine
Arginine
Proline

glycine

Threonine
Serine
glycine
cysteine

this enzyme catalyzes the reaction of Serine into glycine.

Because glycine is an important neurotransmitter, neurological problems will occur.

BH4

PKU
musty urine
hypopigmentation
neurological problems
Increased levels of phenylalanine, phenyllactate and phenylacetate

conversion of phenylalanine to tyrosine.

Tyrosine eventually makes melanin and catecholamines

phenylalanine
phenylacetate
phenyllactate

musty urine smell

If phenylalanine hydroxylase cannot make tyrosine there will be a deficit in catecholamines and thus severe neurologic problems. Supplementing with Tyr and limiting Phe will avoid this consequence.

Deficit in biotin or phenylalanine hydroxylase means no Tyr which is a precursor to melanin. Therefore no melanin and hence no pigmentation.

de novo syn

dietary digestion of proteins

Intracellular digestion of proteins

Protein Synthesis

Degradation / Energy source (NADH / FAD production, TCA intermed, glycolosis, ketone bodies)

Synthesis of other biomolecules (ACH, heme, purines / pyramid, epi, thyroxine, melatoniin)

Cell signaling (neurotransmitter glycine and glutamate)

There is no storage for AA so they get shuttled around in the blood for the 4 uses (energy, synthesis of proteins or biomolecules, cell signaling) and also to get of urea (waste).

Urea (from urea cycle)

Creatinine (creatine phos)

NH4+ (glutamine from kidney)

Uric Acid (purines)

Positive balance
N intake > N excretion

kids growth, preg, lactating, recovery from illness

NEGATIVE Balance

N intake < N excretion

illness and malnutrition

activates trypsin

Self activates at pH of 2 in stomach to make pepsin

activates proenzymes of duodonem

chymotrypsinogen
proelastse
procarboxypeptidase

to make the active digestive enzymes of duodenum

aminopeptidases

dipeptidases

Low albumin indicates decreased ability to digest proteins

Cystic Fibrosis
(due to drying out of pancreatic ducts and failure to deliver digestive enzymes)

Chronic pancreatitis
(enzyme secreting cells of pancreas are shot)

Treatment: supplement with pancreatic enzymes

intestinal epithelial transport

Free AA's go in via Na+ transport

dipeptides go in via H+ transport

In the cell they are broken down to free AA's

urine

absorption mechanism is same in gut as kidney so what is wrong in the gut makes it so kidneys cannot reabsorb either and out they go

AA absorption disease

Cannot absorb COLA in
"lyarge" amounts
Cystine
Ornithine
Lysine
Arginine

Cystine stones form in urinary tract

Extracellular proteins are brought into cells and lysed by cathespins

Ubiquitin marked degradation by a proteosome

transamination reaction

transfers the N group to an a-Ketoglutarate which will eventually deposit it on glutamate.

transaminases and the reverse is aminotransferases

PLP
pyridoxal phos

PLP

Vit B6

Aminotransferases

ALanine aminotransferase
ASpartate aminotransferase

Enzymes that facilitate the transfering of N

From the liver, indicate liver damage as a diagnostic marker

Body needs to get rid of N

Main pathway to get rid of N is aminotransfer to a-keto to eventually glutamate.

GDH catalyzes the removal of N from glutamate AND the placement of N on glutamate for reverse (syn of AA)

NADPH-------->nadp+

NAD+---------->NADH

or

NADP--->NADPH

1). Transamination reactions stick NH4+ on glutamate

2). 3 enzymes "trap" free NH4+

GDH (a-keto + NH4<--->Glu--remember req NADH/NADPH)

Glutamine synthetase
Glutamate + NH4--->Glutamine
remember requires ATP

CPS I
CO2 + NH4 ---> Carbamoyl Phos
remember req 2 ATP

glutamine synthetase

glutamate + NH4 ----> glutamine

requires ATP

1. GDH fixes N to a-keto and this eventually gets put on glutamate.

2). Glutamate is made into Ala

3). Ala travels to liver for break down

1). GDH fixes N on a-keto and eventually makes glutamate

2). Glutamine synthetase uses ATP to make glutamine

3). Glutamine shuttles that N to liver

Digested proteins
purines / pyrimidines
monoamines
deamination of Thr,H,S,Gly

energetics. You use 3 ATP to break bonds in the urea cycle and so if you recycle fumarate in the TCA cycle to make it back into Oxaloacetate , that reaction generates 2.5 ATP via the NAD+--->NADH part

N-acetylglutamate

This enzyme allosterically activates CPS I

Arginine, which is a product of urea cycle, tells body to make more N-acetylglutamate, which revs the urea cycle more.

more active.

no dietary proteins cause the body to break down it's own protein to an excessive amount and so there is increased urea production

too much ammonia=toxic

primary is hereditary (enzymes are wonky)

secondary is due to liver damage / disease so urea cycle is compromised

Type I = CPS I issues

Either CPS I is bunk or you have N-acetylglutamate syn deficiency (remember he's the activator for CPS)

Excess of CO2 and NH4+
Less Carbamoyl Phosphate

issues with ornithine transcarbamylase

More Carbamoyl Phos
Less Citrulline

problem with argininesuccinate synthetase

More citrilline
less arginine succinate

problems with argininesuccinate lyase

more argininesuccinate
less arginine

problems with arginase

More arginine
less urea and ornithine

ASP

low protein diet

scavenger drugs

go throughout body and affix NH4+

benzoic acid + glycine -->hippuric acid-->byebye


phenylbutyrate + glutamine--->phenylacetylglutamine-->byebye

Deficiency in fumarylacetoacetate hydrolase

cannot make fumarate from fumarylacetoacetate so you get a build up of fumarylacetoacetate and succinyl acetone (a metabolite of fumarylacetoacetate) in urine

Pee smells like cabbage
Liver and renal tubule damage

limit phe and tyr

BH4 or phenylalanine hydroxylase

due to tyrosinase deficiency

tyrosine--->melanin disruption

White hair skin, pink eyes

eye and skin sensitivity to light

nystagmus (near or far sighted)

Tyrosine--->Dopa--->Norep, epi

PKU is deficiency in phenylalanine hydroxylase or BH4 so not enough Try is made.

If no Tyr is made no catecholamines is made

Similarly if there is not enough BH4, tryptophan cannot make serotonin

All these guys need BH4!!!

deficiency of homogentisic acid oxidase (just think higher up on the chain than the fumurate bit)

homogentisic acid accumulates in urine and tissues

BAD arthritis in cartilage and pigmentation in eye

homogentistic

The AA's that get broken down into Succinyl CoA (VIThrM) go through a pathway that first hits propionyl CoA and propionyl carboxylase. Prop is a def. in this enzyme

Further down the chain you get to methymalonyl CoA and its enzyme methylmalonyl CoA mutase. A deficiency here also prevents the synthesis of succinyl CoA.

Leads to metabolic acidosis and developmental problems

Methionine. Uses SAM

deficiency in cystathionine sythase which would make cystiene.

so homocysteine builds up (met too)

mental retardation
osteoporosis
dislocation of eye lens
increased risk for MI

further down the homocysteine chain, an enzyme cystathionase is deficient.

no clinical symptoms.

I Love Vermont maple syrup

Isoleucine
Leucine
Valine

maple syrup urine disease

a-keto acid dehydrogenases


insufficient neurotransmitter syn. encephalopathy

reduce the number of branched AA's but they are essential so cannot totally eliminate.

Lack of Tryptophan and niacin from diet

4 D's
dermititis
diarrhea
dimentia
death

high insulin / low glucagon decreases cAMP, leads to less phosphing of PFK-2/FBP-2 complex.

PFK2/FBP-2 complex without P makes PFK-2 active.

PFK2 makes fructose 2,6 bisphos

fructose 2,6 bisphos tells PFK-1 to go and increases rate of glycolosis

PFK-2/FBP-2 complex gets phos'd due to cAMP and protein kinase A action.

phos'd PFK2/FBP2 complex has FBP-2 part active which means no fructose 2,6 bisphos is getting made

PFK-1 not activated

arsenate inhibits the reaction of Glyceraldehyde 3 P dehydrogenase so that the chain ends there and no ATP are produced

Pyruvate kinase

activated by fructose 1,6 bisphosphate

RBC's depend on glycolysis for ATP due to lack of mitochondria.

RBC's need ATP to maintain the flexibility of the plasma membrane and thus if you can't extract that ATP from the reaction catalyzed by pyruvate kinase, RBC's get wonky and destroyed

fructose 1,6 bisphosphate up regulates it

glucagon sets off cAMP, Protein Kinase A and phos's pyruvate kinase. This INACTIVATES it and glycolosis chills

However, if insulin comes along a phosphoprotein phosphatase yanks that P off and reactivates pyruvate kinase

in cells with no mitochondria or very little vascularization.

cornea, lens of eye, kidney medull, WBC's, RBC's

TCA cycle is going all out. Can't accept anymore Acetyl-CoA so the pyruvate builds up and is instead converted to lactate and lactic acid causes cramps

There is no O2 available for aerobic glycolysis, so it switches to anaerobic glycolysis in which lactate is made instead of Acetyl CoA and the build up of lactic acid leads to lactic acidosis

1. Insulin / glucagon ratio impacts production of fructose 2,6 bisphos which regulates PFK-1

2. ratio regulates pyruvate kinase thru phos / dephos

3. levels regulate synthesis of key enzymes of glycolysis (transcription)
glucokinase
PFK-1
Pyruvate kinase

glucose

glycolytic intermediates

Other sugars
(fructose, galactose etc.)

NADPH

Ribose 5-phosphate

Detoxifies

participates in reductive biosynthesis (fatty acid syn, nitric oxide, cholesterol, steroid syn)

nucleotide biosynthesis

The production of NADPH

Production of 5 C sugars
Ribose 5-P

The enzyme that regulates the pentose phosphate pathway.
Glucose 6-Phosphate Dehydrogenase catalyzes the rx of:

glucose 6-Pi--->6-Phosphogluconate

gives off NADPH and H+

NADPH is a product of the rx that Glucose 6-phosphate dehydrogenase catalyzes.

NADPH upon production then competes to bind with GPD6 and thus inhibit it

Insulin (indicates high sugar, can run pentose phosphate pathway) increases gene expression for GPD6

These guys are involved in making the 5 carbon sugars (the nonoxidative reactions in penthose phosphate pathway)

transaldolase transfers 3 c's
transketolase transfers 2 c's

Thiamine pyrophosphate is derived from B1

Thiamine pyrophosphate is crucial to transketolases to make 5 c sugars headed for glycolysis.

Low transketolases = low thiamine pyrophosphate=low B1

oxidative= NADPH

non ox=make fructose 6-P -->glucose 6P-->GPD6-->more NADPH

Ox= NADPH

nonox=ribose 5-Pi

ox=shut down

nonox=make glycolysis intermediates that are made into ribose 5-pi

ox=NADPH

nonox=glycolysis intermediates to get that energy

RBC's

The body uses NADPH to make these superoxides.

They are used in the phagocytes to destroy bacteria

they are highly compartmentalized so they don't do the same thing to the cell!!

vasodilator

anticoagulant

neurotransmitter

antibactericidal

NADPH converts Arg into NO so it can go on its vasodilating etc way

use of NADPH for biosynthetic awesomeness

They are the enzymes that hydroxylate stuff for

1) biosynthesis (ie making bile, steroid hormones or activating Vit D in kidneys)
Mitochondria

2). hydroxylation of drugs or toxins which detoxifies them OR makes them more soluable so they get the hell outta dodge quicker

deficiency of NADPH OR a deficiency of NADPH oxidase.

These patients can't use NADPH or its enzyme to kill those bacteria in the phagocyte and thus they will have persistent infections and will exhibit:

granulomas (build up bacteria)
neutrophil oxidative burst test

In cells, glutathione perioxidase is oxidized in the process of removing H2O2.

NADPH reduces glutathinoe back to it's reduced form to keep on keeping the oxidative stress in cells low.

Tripeptide

uses glutathione peroxidase to detoxify H2O2

Needs NADPH (glutathione reductase) to get reduced after it does its thang

They are carrying O2=oxidative stress!!

NADPH is req by glutathione reductase to reduce glutathione back to oxidize another H2O2

acute hemolytic anemia (oxidative stress)=
fatigue, pallor, shortness of breath

high bilirubin (increased degredation of hemoglobin means heme in blood)=jaundice

High reticulocyte count (immature blood cell production)

oxidative stressors

oxidative drugs
antibiotics--chloramphenicol, sulfamethoxazole
Antimalarias-primaquine, choroquine
Antipyretics and analgesics--acetanilide, aspirin
Vitamin K

fava beans

bacterial infection

Depends upon the remnant activity of G6PD. If you have some G6PD working you have less severe symptoms.

mediterranean has more severe symptoms

Mediterranean has a reduced catalytic activity of G6PD (Vmax)

A- has a reduced stability in G6PD

reduced affinity to NADP+ or glucose 6-Phosphate

pyruvate kinase deficiency (NO ATP)

G6PD deficiency (no NADPH is made)

syn of complex carbs
glycolipids
glycoproteins
glycosaminoglycans

making UDP glucose

galactokinase phos's galactose

2nd step is conversion to UDP-galactose

Galactosemia

galactose 1 Pi / galactitol accumulates in nerve, lens, liver and kidney

remove galactose (lactose) from diet

galactokinase Phos' galactose

leads to build up of galactose (galactokinase deficiency is disease)

galactokinase phos' s galactose

or

aldose reductase reduces galactose to galactitol

the conversion of galactose to galactitol is generally insignificant unless there is another galactose enzyme deficiency leading to a build up of galactose. Then there is more galactitol synthesis than normal and this can lead to cataracts

B-D-Galactosyltransferase

a-Lactalbumin

They come together to make a protein that synthesizes lactose from UDP galactose and glucose

dietary sucrose (table sugar)

fructokinase phos's fructose in liver

aldolase B

This gives you glyceraldehyde and DHAP

These guys are both important in glycolysis, gluconeo, phosphoglyceride (membrane lipids) and triglycerol synthesis (energy storage)

lack of fructokinase

benign, fructose builds up and spills into urine

absense of aldolase B which converts Fructose 1-Pi to glyceraldehyde.

fructose 1-Pi gets trapped in cells

hypoglycemia, vomiting, jaundice, hemorrhage, hepatomegaly, lacticacidemia, hyperuricemia

remove fructose and sucrose from diet

brain

RBC's

Kidney medulla, lens, testes

exercising muscle

These are important tissues, yeah? That's why glucose has to be strictly maintained in blood so these guys can use it for energy to function

breaks down glycogen in liver

makes glucose in liver and kidney cortex via gluconeogenesis

body uses glycogen stores for short term fasting. glycogen stores last about 24 hours, then gluconeogenesis kicks in

No, glycogen stores in muscles is only for the muscles, not the main circulation

UDP- glucose

Glycogenin

glycogen synthase

a1-4 bonds on non-reducing ends of growing chain

4:6 transferase cleaves a 1,4 bond and makes a 1,6 bond, hence the name

glycogen phosphorylase

deficiency of glycogen phosphorylase in SKELETAL Muscles

weakness and cramping of muscles

somewhat benign, chronic condition. liver phosphorylase is unaffected

Has to do with glycogen breakdown, but it's further down the chain than the phosphorylase

lysosome storage disease

glycogen accumulates in lysosmes and causes organ megaly

4:4 debranchers remove the "4" bonds to take off a branch while the 1:6 debranchers release individual free glucose

Glucose 6 phosphatase in the liver. cannot convert glucose 6-Pi to glucose for whole system

glucose 6-Pi translocase

The liver thinks it is in a fed state because the excess glucose and glucose 6-Pi that is not getting converted to glucose 1-Pi, so it thinks it needs to make more glycogen.

Von Gierke Type I

glucose 6- phosphatase

McArdle disease

His glycogen phosphorylase is deficient so he's not breaking down glycogen stores in his muscles for energy.

Not anaerobic that's why no lactic acid

High energy state

High levels of Glucose 6-Pi indiciate a high energy state

The liver will break down glycogen when it senses a low energy state

If there are low levels of ATP or Glucose or Glucose 6-Pi, it will commence breaking down glycogen

High AMP
High Calcium
(both released during exercise)

Low levels of glucose, glucose 6-Pi or ATP

NO

epi will act on muscles in fight or flight moments, but otherwise muscle glycogen is handled in house so to speak

glucagon phosphorylation of enzymes results in degradation of glycogen

insulin dephosphorylation of enzymes results in synthesis of glucagon

glycogen degradation in liver AND muscles

(remember, glucagon doesn't act on the muscles)

insulin dephos's these enzymes of glycogen metabolism

the dephosing of protein phosphatase decreases it's activity and so glucose phosphorylase doesn't break down glucose.

HOWEVER, the dephosing of protein phosphotase increases the activity of glycogen synthase so more glycogen is made

glucagon phos's these enzymes (remember does cAMP)

phosing of phosphorylase kinase increases it's work on glucose phosphorylase and glycogen is broken down to glucose 1-Pi to be used for energy

phosing of protein kinase A slows this enzyme down and thus it inhibits glycogen synthase

makes sense. glucagon is a signal that glycolysis needs to go, not glycogenolysis.

lactate

glycerol

glucogenic AA's (ALANINE)

once glycolysis takes place in the muscles and there is pyruvate, it gets transaminated by ALT to Alanine. The Ala travels to liver where it is reconverted to pyruvate (thanks ALT again!) and eventually made back into glucose via gluconeogenesis.

cori cycle is in exercising muscles and WBC's and RBC's when glucose gets broken down to lactate. lactate goes to the liver and is also made into glucose via gluconeogenesis

Pyruvate-->Oxaloacetate-->Malate-->Oxaloacetate (now in cytosol)-->PEP

enzymes:
pyruvate carboxylase
malate dehydrogenase

biotin

gluconeogenesis (conversion of pyruvate back into PEP by circumventing the irreversible step)

PEP carboxykinase

reoxidizes malate to Oxalacetate in cytosol

Acetyl CoA indicates a high energy state and that biomolecules are being made. Dr fulop will clear up why in the hell this means you want to make sugar.

2nd irreversible step of glycolysis is the reaction from Fructose 6-Pi to Fructose 1,6 bisphos by Phosphofructose Kinase 1

in gluconeogenesis, Fructose 1,6 bisphosphatase dephos's fructose 1,6 bisphosphosphate

High ATP/citrate

When energy is high, there is no need for glycolysis, so we might as well make glucose.

High AMP, or indicator of low energy.

Fructose 2, 6 bisphospate (the stimulator of PFK-1) is inhibitory to gluconeogenesis

Phosphorylated PFK-2/FBP-2 is :
INACTIVE PFK-2, no fructose 2,6 bisphosphate is made so PFK-1 is not stimulated, gluconeogenesis prevails.

lactic acidocis

High levels inhibit the conversion of lactate to pyruvate

Glucose 6-Phosphatase chops off the phosphate from Glucose 6Pi to release free glucose from the liver to the bod.

von Gierke's is a storage disease. Glucose 6 phosphatase doesn't work right so glucose 6 builds up in liver (as does glycogen) and the G6P competes with lactate so it cannot be converted to pyruvate. the hyperlipidemia comes the compensatory low insulin levels from the state of chronic hypoglycemia and so all the food is stored in triglycerides instead of being used in the normal ways

6 ATP and 2 NADH

triglycerides (fatty acids)

glycerol (from adipose tissue in fasting state/ epi or cortisol stress state)

lactate (released from muscles during exercise

gluconeogenic AA's (from muscles in fasting state or cortisol stress

One way which a negative water balance can happen is if there are a lot of solutes in the urine. This causes osmotic diuresis in diabetic patients because they have ketone bodies and glucose in the urine at higher levels. Body will excrete more water as it follows those solutes.

Too much water or not enough solutes. Think long distance runner. They have loss of solutes, thus upon hydration you create a highly hyponatremic plasma environment so the water is going to go in cells and make them swell.

CO2.

Once it is made it is converted to carbonic acid

carbonic acid dissociates to H+ and HCO3-

catabolism of phosphorus containing compounds

metabolism

CO2-- TCA cycle

Catabolism of phosphorus containing compounds

Glycolysis--lactic acid

Fatty Acid oxidation --ketone bodies

HCO3- ECF
HPO4- All cells and main ICF
hemoglobin RBC's

CO2 combines with water and via carbonic anhydrase makes H2CO3. Carbonic acid dissociates in physiological pH, so it releases H+ and HCO3-

measures the difference in concentration of cations and anions in serum

usually 8-12 mEq/L

[Na+] -( [Cl-] + [HCO3-]

if it's higher than normal metabolic acidosis is diagnosed

Fats 9
Carbs 4
Proteins 4
Alcohol 7

for every NADH molecule the body can make several ATP's

Oxidation of NADH= -52.6 kcal/mol

Syn of ATP needs +7.3 kcal/mol

so the math comes out to 7ish ATP's or so.

Food gets metabolized to CO2 and H2O.

Through TCA cycle the electrons get put on NADH and FADH2

These coenzymes pass the electrons down the ETC and the energy they give off drives the production of ATP

(and also gives off heat)

inner mitochondrial membrane

This is the last complex where H+ ions travel through to generate energy to make ATP from ADP.

THey are in the inner mitochondrial membrane

enzymes for TCA cycle reside there

Enzymes for oxidation of fatty enzymes reside there

part of the urea cycle and heme synthesis

mitochondrial DNA and RNA are there.

Matrix of mitochondria because it is part of the TCA cycle
The formation of fumarate from succinate transfers electrons onto FAD to make FADH2.

It DOES not have a proton pump.

protons from NADH get put on complex I via NADH dehydrogenase

coenzyme is flavin mononucleotide (FMN)

FMNH2 (from complex I)

and

FADH2 (TCA cycle)

contains a porphyrin ring with iron

goes from ferric (Fe3+)---> ferrous (Fe2+)

Complex III =cytochrome b

Complex IV = cytochrome a +a3

O2, eletrons and protons are brought together to produce H20.

contains copper

proteins.

they function as enzymes and have either iron or copper for reactions

Each of the complexes (besides complex II) pumps H+ just outside the inner membrane. This creates a electrical and pH gradiant, which as the H+'s flow through the ATP synthase complex turns the turbine that phosphorylates ADP into ATP

sedative and hypnotic

slows down the brain due to lack of ATP creation by interrupting the ETC chain at complex I

insecticide that interrupts the function of complex I in ETC

fungicide that interrupts complex III in ETC

inhibit complex IV

cyanide does this too

Oligomycin

will result in high levels of lactate in blood and urine

If ATP synthase is not working right, there will be a build up of NADH and FADH2 which will accumulate in the matrix. This is a regulatory signal to TCA cycle to stop oxidizing these molecules and pyruvate will thus be shutlled to make lactate instead

complex III

all the electron carriers before the block are fully reduced and everything after the block is still oxidized

uncoupling proteins

proton channel carriers which allow for a H+ "leak"

energy is released as heat

brown fat uses UPC1 or thermogenin to create heat via pumping the protons back through this channel and using the energy for heat. No ATP synthesis when this happens.

2,4--dinitrophenol
was used as a weightloss drug in 30's because you released heat without making ATP=fatal hyperthermia

aspirin, at high doses, uncouples oxidative phos and causes fever

Adenine nucleotide translocase
ADP and ATP shuttle

Phosphate transporter
PO4- shuttle

Glycerophosphate shuttle
brings in FADH2

malate-asp shuttle
brings in NADH

NADH cannot directly go into the inner mitochondrial membrane.

Glycerol 3 Pi gets changed into DHAP (via mitochondrial glycerophosphate dehydrog) and thus FAD gets oxidized to FADH2

oxaloacetate uses NADH to turn into malate (via cytosolic malate dehydrog) and once in the inner membrane, malate gets turned back into oxaloacetate and NADH is recreated

This ONLY happens when the NADH / NAD ratio in the cytosol is higher than in the mitochondria

The malate asp shuttle is more efficient and reversible

mtDNA make more mistakes. Mistakes cannot happen in this chain. If they do they drastically effect tissues that have greater ATP requirements

Liver, Kidney and muscles are greatly affected by these Mitochondrial myopathies

mitochondrial myopathy

neurometabolic disorder that affects the CNS

involves mtDNA made proteins in complexes I - IV

mtDNA inherited degeneration of retinal ganglion cells

mutation in complex I of ETC

results in visual loss in young adulthood

MELAS
Myopathy (mt)
Encephalomyopathy
Lactic
Acidosis
Stroke-like episodes

in 5-15 year olds

strokelike episodes

mutation in tRNA of Leu

LHON

Leber
Hereditary
Optic
Neuropathy

optic atrophy

mutation in NADH dehydrogenase

subacute necrotizing encephalopathy

optic atrophy, ophthalmoplegia, nystagmus, respiratory issues,ataxia, hypotonia, spacticity and developmental delay

mutation in Fo subunits of FoF1ATPase

partial reduction of O2 by complex IV could lead to O2-

CoQ reduction in complexes I and II can also make O2-

~2% of cellular O2 becomes O2-

enzymes: superoxide dismutase, catalase, glutathione perioxidase / reductase

kill pathogens

make hypochlorus acid in neutrophils and macrophages

bacteria is brought into phagosome inside neutrophil

NADPH oxidase creates O2- from O2

this gets turned into H2O2 and connected to Cl to make hypochlorus acid which kills bacteria.

CGD or Bridges-Good syndrome

mutation in NADPH oxidase so it cannot make ROS's in phagosome in neutrophil.

These patients cant kill the bacteria using O2- so they have chronic infections by catalase + microorganisms

combines electrons, protons and O2 to make H2O

1). primary disorder is increased production of H+ by tissues
increased H+, decreases pH

2).H+ protons are combined with HCO3- to get buffered
HCO3- decreases

3). body compensates by hyperventilating CO2
pCO2 goes down due to this compensation

1). Primary disorder: Hyperventilation
decrease in H+
decrease in pCO2
pH increases

2). Blood CO2 is decreased

HCO3- is decreased because you are losing so much CO2, HCO3- is pulling H+ out of system to keep up with making that CO2. That's also why blood H+ is dropping.

1). Primary disorder: crappy breathing. CO2 is not being expired properly
pCO2 is increased, H+ is increased
pH is decreasing

2). balance with carbanic acid goes in direction of making more HCO3- and H+ because of all the CO2 around
HCO3- increasing, H+ increasing
pH decreasing

1). Primary disorder: prolonged vomitting cause excessive loss of H+ and volume depletion
Blood H+ is decreased, pH is increased

2). HCO3- is increased to try and replace H+ losses

3). hypoventilation compensation to raise pCO2 levels to make more H2CO2 to make more H+

H2PO4- binds with H+ (that are given off from carbanic acid)

HCO3- binds with H+ to make H2CO3

H+ binds to Hb to make it HbH which favors unloading (T state) of Hb

carbanic anhydrase

You are exchanging CO2 in the lungs so the equilibrium of the CO2 equation is going to cause more bicarb to bind with H+ to make H2CO3 to replace the CO2 that is leaving outta the lungs

H2PO4- dissociates into H+ and HPO4 (2-)

If the intracellular environment becomes too acidic, H+ is pumped out in exchange for Na+ ions

If it becomes too basic, more bicarb is transported out in exchange for Cl- ions

Ammonia (NH3) combines with H+ and becomes NH4+

bicarb

respiratory alkalosis followed by complex metabolic acidosis.

hyperventilating will lead to the respiratory alkalosis and dissociation of salicylic acid leading to direct interference with mitochondrial ATP production
other acids accumulate

transported from the cytoplasm into the mitochondria

Then pyruvate dehydrogenase complex does its thang.

conversion of pyruvate to Acetyl CoA

No, not a part of TCA cycle. 1st step of cycle is the condensation of Acetyl CoA with Oxaloacetate to form citrate

Basically everything filters down to it

degradation of fatty acids
alcohol metabolism
glycolysis (main one)
glucose alanine cycle

converting pyruvate to oxaloacetate

pyruvate dehydrogenase complex

irreversible

E1=thiamine pyrophosphate

E2= lipoic acid and CoA

E3= FAD and NAD+ (niacin)

pyruvate dehydrogenase kinase

pyruvate dehydrogenase phosphotase

heart

skeletal muscle

nervous system

Thiamine is pretty stinkin' important

low energy signals (CoA, Pyruvate, NAD+) tell the cycle we need to run.

protein kinase part of enzyme is inhibited so PDH complex is not phos'd and TCA cycle runs

High energy signals (ATP, Acetyl CoA, NADH) tell the enzyme we don't need to make more ATP. The protein kinase portion of the complex phos's E1 and it is locked down.

Ca++ is a strong activator of the phosphorylase. It whips that Pi off PDH complex so it can go, go, go

This makes sense when you think about skeletal muscle and all the stimulatory effects of Ca++. In active muscles, you have Ca++ and you need TCA cycle to go, so it makes sense Ca++ would activate the phosphorylase which in turn activates PDH complex

Pyruvate cannot be converted to Acetyl CoA.

Pyruvate is instead shunted to lactic acid and the brain and CNS suffer because they rely on TCA cycle for ATP

PDH complex

a-ketoglutarate dehydrogenase

a-keto-acid dehydrogenase

arsenic binds to thiol of lipoic acid and makes it unavailable for the above enzymes

This means cells are in a HIGH energy state

Inhibits PFK-1 (inhibits glycolysis)

Stimulates gluconeogenesis (because it takes a lot of energy to make glucose, might as well use some that we have lying around)

Synthesize some FA's

products of TCA cycle further down the line (citrate, NADH, succinyl CoA)

Isocitrate to a-ketoglutarate

Isocitrate dehydrogenase

ADP activates it

Ca++ activates it

High energy stuff inhibits it like ATP or NADH

thiamine pyrophosphate

lipoic acid and CoA

FAD and NAD+

look familiar? Same cofactors as PDH complex

Ca++ lying around indicates that a cell is exercising and will need ATP, so go TCA cycle

PDH complex and a-ketoglutarate dehydrogenase both need lipoic acid (which arsenic binds to the thiol of to competitvely inhibit it) but only the a-ketoglutarate dehydrogenase is in the TCA cycle

Succinate -->succinate dehydrogenase-->Fumarate

FADH2 is generated for ETC

fumarase

malate dehydrogenase turns malate into oxaloacetate

reversible and is activated by high levels of NAD+

TCA cycle (malate to oxaloacetate via malate dehydrogenase)

transamination of Asp

Carboxylation of pyruvate

Our City Is Kept Safe and Sound From Malice

Oxaloacetate
Citrate
Isocitrate
a-Ketoglutarate
Succinyl CoA
Succinate
Fumarate
Malate

3 ATP from every NADH

There are 9 ATP produced from the 3 NADH' s in TCA cycle

2 ATP

GTP

citrate synthase

isocitrate dehydrog

a-ketoglutarate dehydrog

If ADP increases it activates reactions that generate ATP (like TCA cycle)

It ramps up production of ATP until the rate of ATP production matches ATP consumption

If there is no ADP or Pi around you can't very well make ATP

NADH and FADH2 stop getting oxidized and they accumulate

low NAD+ / NADH ratio because the NAD+ needs to be around for the dehydrogenases that require it.

flow of information from DNA to RNA to protein is termed the central dogma.

The 5 membered ring with a base attached to it but no phosphates

sugar + base + pi's

A and T (U)

C and G

double helix with 2 chains coiled around a common axis
5' to 3' and then antiparalell 3' to 5'

RNA

heat does DNA