BLOCK&4&!

Nitrogen&Metabolism&

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Branch!Chain!Amino!Acids!(BCAAs)!are!

utilized!by!skeletal!muscle!!

In!Fasting!Conditions:!

Ala!!liver!

Carbon!utilized!in!gluconeogenesis!

Nitrogen!utilized!in!urea!cycle!

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Gln!liver,!kidneys!and!intestine!

Nitrogen!used!in!urea!cycle!

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Protein&degradation&

PEST—proline,!glutamate,!serine!and!threonine!have!short!halfHlives!

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1.!Degraded!in!the!proteasome!with!ubiquitin!tag!covalently!bound!to!the!

εH!NH2!of!lysine!

2.!Degraded!by!calpainHbinding!to!the!protein—autolysis!to!become!

smaller,!active!but!unstable!proteolytic!enzyme!

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Nitrogen&Balance&

N!leaving!=!N!entering!usually!

! Positive!balance!in!growth!and!pregnancy!

! Negative!balance!in!cancer,!trauma!and!surgery!

Nitrogen’s&Main&Destinations&

Three!factors:!

1. Body!Protein!Turnover!

2. Pool!of!Free!AA’s!

3. Nitrogen!Balance!

!Amino!Acid!Catabolism!

1. Removal!of!–NH2!group!via!transamination!–

mostly!in!the!liver!(requires&PLP);!!

o requires!pyruvate,!OAA!or!αHKG!as!acceptor!

o produces!alanine,!aspartate!and!glutamate!

o Lysine!and!Leucine!are!ketogenic!

o Glutamate!can!be!oxidatively&deaminated&or&

reductively&aminated&via&GLUTAMATE&

DEHYDROGENASE&&

o Requires&NADPH&for&reduction&and&NAD+&

for&oxidation&

o Oxidation&activated&by&ADP&and&GDP&

o Oxidation&inhibited&by&ATP&and&GTP&

2. Amino!acids!enter!glycolytic!or!TCA!catabolism!

!

Schiff!Bases—compound!with!an!N=C!group!

PLP&is&a&prosthetic&group&bound&to&lysine&(Schiff&base)&

PLP!is!made!through!reduction!of!pyridoxine!and!then!ATPHdependent!

phosphorylation!of!pyridoxal!

Glutamate!is!the!sole!amino!acid!that!accepts!free!NH3!

!

Glutaminase!in!liver!mitochondria!produces!toxic!free!NH3!from!glutamine!

Glutamine&Synthetase!produces!glutamine!from!glutamate!

! Requires!NH4!and!ATP!

! Detoxifies!NH3—only&amino&acid&that&accepts&free&ammonia!

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DOamino&acids&

Essential!in!mammalian!diets!

Catabolized!by!DHamino!acid!oxidase!(in!peroxisomes;!requires!FAD)!

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Heme&Metabolism&

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&Heme!

Ferrochelatase& Fe2+!

Cyclization—!

4!methenyl!bridges!

3!Porphobilinogen!

Hydroxymethylbilane!

Succinyl!CoA!

2�HALA!!

Glycine!

Porphobilinogen!

�OALA&Synthase&

PLP&

CO2!+!CoASH!

�OALA&

Dehydratase&

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Porphobilinogen&

Deaminase&

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Uroporphyrinogen!III!

Uroporphyrinogen&

III&Cosynthase&

Coproporphyrinogen!III!

Protoporphyrinogen!IX!

Protoporphyrin!IX!

Plant!porphyrins!are!the!major!source!of!Mg2+!in!human!diets!

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Heme!is!synthesized!in!bone!marrow!and!in!the!liver!

! !Necessary!for!CYP450!production!

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*Exergonic*&

Zn2+&

NonOerythropoietic&

tissue—Liver&&

Iron&deficiencyOONonO

allosteric&inhibition&

in&bone&marrow&

Hematin—Fe3+&&

Pb2+&

Congenital&

Erythropoietic&

Porphyria&

Acute&Intermittent&

Porphyria&

δOALA&Dehydratase&

Porphyria&

Porphyria&Cutanea&

Tarda&

Hereditary&

Coproporphyria&

Variegate&

Porphyria&

Erythrogenic&

Protoporphyria&

CEP!is!the!only!porphyria!that!is!autosomal!recessive!

Photosensitivity—abnormal&porphyrin&isomers&develop&

Scarring,!infections,!loss!of!facial!features!and!digits,!hemolytic!

anemia,!erythrodontia!

&

In!Bone!marrow,!

!Buildup!of!phototoxic!intermediates!that!are!not!easily!excreted!

!Photosensitivity!

! AIP&(hydroxymethylbilane&synthase&deficiency)&

No&photosensitivity&

Acute!abdominal!pain,!circulatory!and!neuropsychiatric!

disturbances,!kidney!and!liver!effects,!extremity!pain!

Seizures,!insomnia,!hysteria,!disorientation,!hallucinations!

For!hepatic!porphyrias,!hemin!is!a!possible!treatment!

Also!avoid!direct!sunlight!and!ingest!βHcarotene!

Heme&Breakdown&&

Hemoglobin!is!degraded!to!heme!and!globin!

Heme!is!then!broken!down!into!Fe3+,!CO!and!biliverdin!

! USES&NADPH&(1);&Occurs&in&macrophage&

Biliverdin!gets!reduced!to!bilirubin!

! USES&NADPH&(2);&Occurs&in&macrophage&

Bilirubin!is!transported!via&albumin!to!the!liver!where!it!

binds!ligandin&(has&glutathioneOSOtransferase)!

Bilirubin!becomes!conjugated!with!2!glucuronates!via!UDPH

glucuronate!and!is!converted!to!bile!!

Bile!is!excreted!as!urobilinogen!or!stercobilin!

DubinOJohnson&syndrome—inability!to!secrete!bilirubin!into!

bile!

Nucelar&Jaundice—bilirubin&accumulates!in!lipid!rich!areas!

of!brain!CNS!problems—not!conjugated!

Neonatal&Jaundice—naturally&occurring&glucuronyl&

transferase&deficiency&

Hemolytic&Jaundice&occurs&during&massive&lysis&of&RBCs&

such&as&in&malaria,&sickle&cell!

! !

Uroporphyrinogen&

Decarboxylase

Photosensitivity,!labial!

grooves,!liver!damage!

Most!common!

Photosensitivity!

Red!brownHurine!

Urea&Cycle&

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Ornithine!

Citrulline!

Mitochondria&

Pi!

CO2!+!H2O!

HCO3H!+!NH4!

Carbamoyl!

Phosphate!

Carbamoyl&

Phosphate&

Synthetase&I&

(CPS&I)&

Mitochondria&Ornithine&

Transcarbamoylase&

Citrulline!

Ornithine!

Argininosuccinate!

Aspartate!

ATP!AMP!+!PPi!

Arginine!

Fumarate!

H2O!Urea!

Cytosol&

Argininosuccinate&

Synthetase&

Argininosuccinate&

Lyase&

Arginase&2!ATP!

2!ADP!

Glutamate! Acetyl!CoA!

NHAcetylHGlutamate!

Arginine!

Acetate!+!

Glutamate!

Hydrolase&

1st&Nitrogen&comes&from&free&

NH4&of&glutamine/glutamate&

deamination&

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2nd&Nitrogen&comes&from&

aspartate&

Blood&Urea&Nitrogen&(BUN)&

Measurements!of!blood!urea!can!be!

clinically!significant!in:!

! Liver!failure—low!or!normal!BUN!

! Kidney!Failure—sharp!rise!

Urea&Cycle&Failure&

OTC&deficiency&(xOlinked)!is!the!most!common!urea!cycle!deficiency!

Orotic!Acid!Buildup;!hyperammonemia!&!encephalopathy!

If!in!neonate—feeding!problems,!vomiting,!lethargy,!poor!CNS!development!

Dietary!protein!aggravates!condition!

Glutamine!buildup!causing!limited!availability!of!αHKG!for!TCA!cycle!function!causing!

depleted!ATP!

! More!ATP!is!used!in!the!glutamine!synthetase!reaction!to!detoxify!NH3!

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Liver!Failure:!Muscle!creates!toxic!NH3!from!utilization!of!BCAAs;!Muscle!releases!

amino!acids!!

! Aromatic!amino!acids!accumulate!&!damage!nervous!tissue!causing!hepatic!

encephalopathy!

Kidney!Failure:!Urea!and!creatinine!accumulate!in!plasma!

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Ammonia!is!also!produced!from!

bacterial!digestion!in!the!gut!

(bacterial!urease)!

NH3!is!higher!in!portal!circulation!

than!systemic!circulation!

Amino&Acid&Degradation&

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The!Ketogenic!amino!acids!are!leucine!and!lysine!

The!glucogenic!and!ketogenic!amino!acids!are!tyrosine,!!

isoleucine,!phenylalanine!and!tryptophan!

Transamination&Reactions&

!

Pyruvate! ! ! Alanine!

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αHKG!! ! ! ! Glutamate!

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Oxaloacetate! ! ! Aspartate!

PLP&Requirement&

Asparagine!

Asparagine&Synthetase&

*Amination!with!glutamine!as!

a!donating&group&

Requires&2&ATP&

Asparaginase&

*Deamination!

resulting!in!free!

NH4!group!

!

NH4!+!H2O!

Glucose!

3HPG!

2HPG!

Pyruvate!

Glycine!

Serine!

Cysteine!

Alanine!

SO4!

Serine&

Dehydratase&

Serine&HydroxyO

methylO

transferase&

FH4&

N5,N10&Met&FH4&

CO2!+!NH3!

FH4&

N5,N10&Met&FH4&

NAD+&

NADH&

Glycine&

Cleavage&

Enzyme&

Tetrahydrofolate!is!

created!from!folic!

acid!(Vitamin&BO9)!

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Formation!requires!

2!reductions!from!

Dihydrofolate!

Reductase&

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Requires!2&NADPH!

Threonine!PLP&&

Glyoxylate!Oxidase&

Transaminase&

H2O2&+&

NH4+&Oxalate!

Glycoxalate!

TPP&

O2&

Oxalic&Acid&

creates&

precipitates&in&

renal&tubule&

αHketobutyrate!

Threonine&

Dehydratase&NH3!

FH4&NH4+!

Glucose! αHKG! Glutamate! Glutamate!Semialdehyde!

Proline!

Ornithine! Arginine!Histidine! Formaminoglutamate!

Glutamine!

&Histidase&&

*Deficiency!causes!motorHmental!retardation!

Methionine! Homocysteine! Cystathionine!

SAM!

SAH!

B12—CH3!B12!

FH4!N5,N10—CH3HHFH4!!

THF!is!required!to!recycle!

B12!

Folate!Trap!if!MeFH4!is!

inaccessible!

Pernicious&Anemia&

B12&deficiency&

Serine!

Cysteine!

PLP&&

PLP&&

Cystathionine&Synthase&

Homocystinuria—accumulation!of!

homocysteine,!homocystine!and!

methionine!

Funnel!Chest!

Marfan!like!limbs!

Tx:!High!B6!doses!

Taurine!

Cysteine&

Sulfinate&

Decarboxylase&

PAPS!

*SO4!+!

3!ATP!

FAD!

!

FADH2!

NADP+!

!

NADPH!

NADPH!!!!NADP+!

NADH!!!!NAD+!

*Semialdehyde!

cyclization!

contains!stable!

Schiff!Base!PLP&&

Cystinosis&

Defective!Lysosomal!Transporter!

Cystine!crystals!in!lysosomes!

Photophobia,!tearing,!blindness,!!

polyuria,!glucosuria!

Goes!

to!

PMS!

BCAAs&&(degraded&in&muscles&primarily)& & & & & & Aromatic&Amino&Acid&Synthesis/Degradation&

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Valine! Isoleucine! Leucine!

αHketoisocaproate!αHketoisocaproate!αHketoisocaproate!

CO2!

NADH!

CO2!

NADH!

CO2!

NADH!

Isobutyryl!CoA! 2!Methylbutyryl!CoA! Isovaleryl!CoA!

Propionyl!CoA!

Acetyl!

CoA!HMG!CoA!

Acetoacetate!

2!NADH!

FADH2!FADH2!

Succinyl!CoA!

Methylmalonyl!CoA!

Glucogenic:!Valine,!Isoleucine!

! Makes!Succinyl!CoA!

Ketogenic:!Isoleucine!and!Leucine!

! Makes!acetoacetate!and!acetyl!CoA!

2!NADH!

αOketoacid&DH&

Maple&Syrup&

Urine&Disease&

*founder!effect!

Maple&Syrup&Urine&Disease&

Severe!mental!retardation,!acidosis,!sweetH

smelling!urine,!early!death!frequent!

Treatment:!Thiamine!and!restricted!BCAAs!in!

diet!

TPP& TPP& TPP&

Lysine!

Carnitine!

3!SAM!

Phenylalanine!

Tyrosine!

pHhydroxyphenylpyruvate!

Homogentisate!

Fumarate! Acetoacetate!

Phenylalanine&Hydroxylase&

½&O2&and&BH4&

Requires!PO4!on!serine!from!cAMP!to!

make!dimer!a!tetramer!

Requires!Fe2+!!

Tyrosine&

Aminotransferase&

Ascorbic&Acid&

Homogentisate&

Oxidase&

Fumarylacetoacetate&

Hydrolase&

Phenylketonuria&(PKU)&

Accumulation!of!phenylalanine,!!

Phenylpyruvate!and!phenylacetate!

Aberrant!from!splice!or!missense!R!W!

Deficient!BH4!is!malignant&PKU!

Treat!with!very!restrictive!diet!

Tyrosinemia&&II&

Alkaptonuria&

Accumulated!homogentistic!acid!

Black!Urine!

Ochronosis—dark!pigments!in!CT!

Tyrosinemia&I&

CabbageHlike!odor,!Impairment!of!!

tubular!absorption!&!liver!failure!!

BH4!needs!to!be!recycled!

through!dihydropteridine!

reductase&

Using&NADPH&or&NADH!

Tryptophan&Degradation&

1st!step:!cleavage!of!pyrrole!ring!by!pyrrolase&

& Requires!O2!and!NADPH!

Used!to!form!Niacin/&Nicotinic&Acid!

Products.!Kynurenate!and!xanthurenate!are!

excreted!through!urine!

Phenylpyruvate!

Phenyllactate!Phenylacetate!

Phe&and&its&metabolites&cross&

placental&barriers&and&cause&

microcephaly,&cardiac&defects,&

low&IQ&

THB&is&specifically&

used&with&aromatic&

compounds&

Tyrosine!is!a!precursor!to!!

• catecholamines!

• Thyroid!hormone!!

• Melanin!

Biogenic&Amines&and&Nitrogenous&Compounds&

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Arginine:&Creatine!Sythesis!and!Nitric!Oxide!

Creatine:&Provides!immediate!source!of!ATP!due!to!high!energy!phosphate!bond&

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Creatine&Synthesis&&

Kidney!is!site!of!guadininoacetate!formation!

Liver!and!Pancreas!are!sites!for!SAM!addition!

Muscle!has!an!NA+!drive!transporter!for!creatine!uptake!

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Arginine! Citrulline!

NADPH!!!!!!!NADP+!

O2! NO!

Glycine! Guanidinoacetate!

Arginine!

Ornithine!

Creatine!

SAM!

SHadenosyl!Homocysteine!

(SAH)!

Creatine! Creatine!Phosphate!

ADP!ATP!

Creatine&

Phosphokinase&

Creatinine!Spontaneous!

cyclization!

*Creatinine!is!excreted!

through!urine!

Nitric&Oxide:!Vasodilation,!blocks!platelet,!

aggregation,!neurotransmitter,!

inflammation!and!immune!response!

through!guanylate!cyclase!activation!

VIAGRA—inhibits&guanylate&

phosphodiesterase,&prolonging&

cGMP&halfOlife!

Glutamate:!!

GABA!formation!through!

nonHoxidative!

decarboxylation!

! PLP&Required&

Opposite!carboxylase!

reaction!also!requires!

PLP&

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GABA=&inhibitory&

neurotransmitter;&

uptaken&in&Glial&cells!

Histidine:!!

Histamine!formation!using!histidine&

decarboxylase&(Requires&PLP)&

Histamine!deactivated!through!deamination!

(Diamine&Oxidase)!in!periphery!tissues;!

methylation!(SAM),!then!deamination!in!the!

brain!(MAOOB)!

! Deamination!forms!free!NH4+!

!Tryptophan:!

Serotonin!formation!through!tryptophan&hydroxylase!

(requires&BH4&and&O2)!and!then!Dopa&Decarboxylase&(PLP&

required)&!

Serotonin!modulates!mood,!emotion,!appetite!!

Inactivated!by!MAO&

Flibanserin—serotonin&antagonist;&Female&viagra&

!

Serotonin!produces!Melatonin!through!addition!of!acetyl!

CoA!and!then!methylation!(SAM)!

Melatonin!is!a!strong!antioxidant!that!is!secreted!in!a!

circadian!manner;!blocks!LH!and!FSH!(Rapidly!cleared!

by!liver)!

Alzheimer’s&treatment—prevents!

hyperphosphorylation!of!Tau!proteins!

Tyrosine:!

Catecholamine!Synthesis!

Tyrosine!

Dopa!

Dopamine!

NE!

Epi!

Tyrosine&

Hydroxylase&

Dopa&

Decarboxylase&

Dopamine&βO

hydroxylase&

Phenylethanol

amine&NOmet&

transferase&

BH4&

Cu2+&

PLP&

Cu2+&

Vitamin&C&

SAM&

Degradation!through!catecholOOO

methyltransferase&(COMT)&

[Requires&SAM]&and!Monoamine&

Oxidase&(MAO)&

&

Excessive&degradation&causes&

depression!

Parkinsons&Disease&

Destruction!of!CNS!cells!

that!synthesize!dopamine!

Bradykinesia,!cogHwheel!

like!movements!

Thyroid!Hormone!

Synthesized!from!tyrosine!

residues!bound!to!

thyroglobulin!

Requires&H2O2&

Goiter—enlarged&

thyroid&to&salvage&iodine&

Tyrosine!creates!melanins&

Tyrosinase&(Cu)!produces!

Dopaquinone!in!presence!of!

UVB&light!!

Dopaquinone!+!cysteine!!

Pheomelanin!Eumelanin!

!

Pheomelanin!=!pinkHred!in!

skin!and!red!hair!

(carcinogenic)!

Eumelanin!=!black/brown!

Neuromelanin!in!substantia!

negra!(antiHROS!activity)!

Purines&

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RiboseH5!P!from!HMP!shunt!

provides!the!backbone!!

3!Common!AAs:!aspartate,!

glutamine,!glycine!

AMP!

Aspartate!

GTP!

!

RiboseH5HP!

PRPP!

PRPP&

Synthetase&

2!ATP!

!

AMP!Glycine!+!ATP!

N10HFormylHFH4!

Glutamine!+ATP!

CO2!

Aspartate!+!ATP!

N10HformylHFH4!

IMP!ATP!

Glutamine!!

Glutamine&Phosphoribosyl&

Amidotransferase!

activates!PRPP!to!5H

Phosphoribosyl!1Hamine!by!

adding!an!amido!–NH2!from!

glutamine!

Inhibited&by&nucleotides&

THF!

!

IMP&

DH&

& GMP&

synthetase&

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Adenylosuccinase&

Adenylosuccinate&

Synthetase&

Mycophenolic&Acid&

Uncomompetitive!inhibitor!

Deprives!T!and!B!cells!of!

nucleic!acids!

Prevents!graft!rejection!

Fumarate!

NAD+&

Adenylate&Kinase&

AMP!+!ATP!!!2!ADP!

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Guanylate&Kinase&

GMP!+!ATP!!!GDP!+!ADP!

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NDP&Kinase&

GDP!+!ATP!!!GTP!+!ADP!

CDP!+!ATP!!!CTP!+!ADP!

!

GMP!

GDP!

ADP!

PURINE!SALVAGE!PATHWAY!

5’&nucleotidase&

5’&nucleotidase&

Pi!

HGPRT&

HGPRT&

APRT&Pi!

Adenine! AMP! Adenosine!

Hypoxanthine!

Guanine! GMP!

IMP!

Guanosine!

Inosine!

PRPP! !!!!!!PPi!

Purine&Nucleoside&Phosphorylase&

Adenosine&

Deaminase&

AMP&

Deaminase&

Adenosine&Kinase&

ADP! !!!!!!ATP!

PRPP! !!!!!!PPi!

PRPP! !!!!!!PPi!

5’&nucleotidase&

Pi!

NH3!

Ribose!1HP!

Ribose!1HP!

!

Purine&Nucleoside&

Phosphorylase&Xanthine!Uric!Acid!

Xanthine&Oxidase&

Xanthine&

Oxidase&

Allopurinol&Tophaceous&Gout—Poor!

solubility!of!urate!

Urate!crystals!in!leukocytes!and!

in!joints!(arthritis)!

Treatment:!Allopurinol!

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H2O2! !!!!!!O2!

Competitive&

Lesch&Nyhan&

HPGRT!mutation!

Accumulation!of!hypoxanthine!and!

guanine!

Chewing!of!fingers,!lips!and!tongue!

Uric!crystals!in!urine!

ADA&Deficiency&

SCID!

High!dAdenosine!levels!

Ribonuceotide!reductase!

insufficient!

T,!B!and!NK!cells!

deficient!

Purine&Nucleoside&Phosphorylase&Deficiency&

Accumulation!of!guanosine!and!inosine!

Affects!T!cells!

Ring!is!indestructible!

Molybdenum&

Pyrimidines&

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Pi!

Glutamine!+!CO2!+!2ATP!

Carbamoyl!Phosphate!

Orotate!

OMP!

CPSOII&&

(in&cytosol)&

Aspartate!

PRPP!

!

CO2!

UTP!

PRPP!

UMP!

OMP&decarboxylase&

Orotate&

Phosphoribosyl&

Transferase&

Orotic&Aciduria&

UMP&synthase!deficiency!

Poor!growth,!megloblastic!anemia!

High!orotate!in!urine&&

ATP!is!used!to!add!

phosphates!to!NMP!and!

NDPs!!

Also!required!in!amide!

transfers!

UDP!

UTP!

CTP!

CDP!

dCDP!dCTP!

dTTP! dTDP!

dTMP!

dUMP!

dUDP!

RR&

RR&dCMP!

NH4+!

N5,N10—MethyleneHFH4!

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FH2!

Glutamine!

Only!NDP!is!reduced!

CTP&Synthetase&

Pyrimidines!are!degraded!to!!βHalanine!

and!βHaminoHsuccinoHbutyrate!which!

become!acetyl!coA!and!succinyl!CoA!

Ribonucleotide&Reductase&(RR)&

Contains!thioredoxin—!2!–SH!groups!in!!CysH

GlyHProHCys!sequence!

Requires!NADPH!and!Thioredoxin!

reductase!in!order!to!revert!

thioredoxin!back!to!useable,!HSH!form!

Only!acts!on!NDPs!

Enzyme!has!2!sites:!R1!and!R2!

! R1:!Binds!NTP!and!specifies!NDP!to!be!

reduced!

! R2:!Catalysis!(reduction!activity)!

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FH4!

DHF&Reductase&

Methotrexate&

5OFluorouracil&

(5OFdUMP)&NADPH&

Thimydylate&Synthase&

Pyrimidine&Defects&

Dimers—occur!from!UV!light!exposure!

O2H!and!OHH!radicals!

Defective&UVOspecific&endonuclease&

(uvrABC&exinuclease)&can!cause!

mutations!and!cancer!

Methylated!Cytosines!(via!SAM)!

spontaneously!deaminate!and!

become!thymines—base!pair!

mutations!

! Causes&underOrepresentation&of&

methylated&cytosines&in&

humans&

! **Note:!Methylation!causes!

weaker!H!bonding!causing!

opening!for!polymerases!to!work!

Pyrimidine!Ring!contains!amide!from!glutamine,!CO2!and!aspartate!backbone!

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Calcium&and&Phosphorus&

Calcium!Phosphate—bones!and!teeth!

Ca2+—neuromuscular!function,!membrane!work,!signal!

pathways!(Calmodulin),!cofactor!in!clotting!

cascade!!

Plasma!calcium!increased!by!PTH!(parathyroid)—Bone!

resorption,!Increased!gut!and!renal!absorption!

Plasma!calcium!decreased!by!calcitonin!(thyroid)—

Calcium!deposition!in!bone,!Decreased!renal!

reabsorption!

Phosporus!follows!Calcium!

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Sodium,&Potassium,&Chloride&

Electrochemical!gradient,!acidHbase!balance,!fluid!volume,!

antibiotic!defense!

Na+!influences!blood!volume!and!blood!pressure,!however!

lower!sodium!diets!don’t!help!blood!pressure!due!to!

intracellular!Na!stores!being!taken!out!

ClH!is!essential!in!acid!base!balance,!digestion,!antibacterial!

defenses!of!macrophages!and!eliminating!CO2!

(HCO3/ClH!exchanger)!

Trace&Minerals&

Most!complex!with!specific!intracellular!binding!proteins—storage!and!scavenging!of!reactive!metal!

ions!

Pb&poisoning—lead!replaces!many!other!divalent!metals;!interferes!with!protein!shape,!and!protein!

functioning!in!gene!control!(Issue!stems!from!Low&Km)!

!Copper!

Stored!in!liver!

60%!bound!to!ceruloplasmin;!

rest!with!albumin!or!

histidine!complex!

Ceruloplasmin!rises!in!

hyperglycemia!causing!

Wilson’s&Disease&

Used&in&Cytochrome&Oxidase,&

dopamine&βOhydroxylase,&

tyrosinase,&lysyl&oxidase&

superoxide&dismutase&

Deficiency!=!Menke’s&Disease!

(XR)!

! Brittle!Hair,!mental!

retardation,!seizures,!

arterial!aneurysms!

! Microcytic&Anemia&

! Deficient&ATP&dependent&

Cu&transporter&

Toxicity!=!Wilson’s&Disease&(AR)!

! Biliary&Cu&excretion&

blocked&

& Liver!and!Brain!damage!

Zinc&

Used&in&carbonic&anhydrase,&

Cytosolic&superoxide&

dismutase,&alcohol&

dehydrogenase,&ALA&

dehydratase,&DNA&and&

RNA&Polymerases&

Sources:!meat,!nuts,!beans!

Transported!through!albumin&

Metallothionein—main!stores!of!

zinc!

! Induced!synthesis!by!heavy!

metals!

! Helps!gut!absorption!

! Protects!cell!from!toxic!

unbound!metal!ions!

Deficiency:!poor!growth,!testicular!

atrophy,!delayed!sexual!

development,!poor!wound!

healing!DERMATITIS!

Acrodermatitis&Enteropathica—

dermatitis,!hair!loss!

(alopecia),!diarrhea&

Manganese&

Mito.&Superoxide&

Dismutase&

Toxicity:!Psychosis!and!

Parkinsonism&

“Mn&Madness”&!

Molybdenum&

Xanthine&Oxidase&

Selenium&

Mainly!in!selenocysteine!

in!glutathione&

peroxidase&

Keshan&Disease—

cardiomegaly,!

impaired!ROS!

defense!

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Chromium&

“Glucose!Tolerance!

Factor”!

Facilitates!insulin!action!

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Fluorine&

Strengthen!bones!&!teeth!

Prevents!osteoporosis!

Iron&

Uptake!stimulated!by!alcohol!

Mostly!in!Hb;!Otherwise!bound!to!ferritin!and!

hemosiderin!in!liver,!spleen,!bone!marrow,!gut!

mucosa,!pancreas!

Toxic!when!in!free!state:!free!radicals!and!protein!

disruption;!LDL!oxidation!and!CV!disease!

Ferritin!!

! H!(heart)!and!L!(liver)!subunits!!

! Hollow!core!stores!Fe3+!as!FeOOH!crystals!

! Most!abundant!storage!form!at!low&Fe&stores&

& Apoferritin!has!little!bound!iron!

Hemosiderin!contains!same!subunits!as!ferritin!and!

stores!Fe3+!but!is!SOLUBLE!

! Predominant!at!high&Fe&stores&

Ferritin—binds!Fe3+!at!2!sites!

! Origin!is!β!globin!and!spleen!is!predominant!

locationdue!to!RBC!lysis!

TransferrinHFe!binds!to!receptor!and!is!endocytosed—

lysosomes!dissociate!Fe!from!transferrin!

! Fe3+!is!reduced!by!duodenal!CypB—ferric!

reductase!(Vit&C)!

! Fe2_!transported!to!cytosol!by!transporter!

Refsum’s&Disease—Phytic!Acid!blocks!Fe3+!reduction&

Deficiency:!Acute!and!hemorrhage;!hemolytic!anemia,!

microcytic!anemia!(small!RBCs);!anemia!

common!in!children!and!menstruating!women!

Toxcity:!Hemosiderosis—free!radical!formation!

! Hemochromatosis!(ARHchrom!6):!organ!

damage,!hyperpigmentation!

UVA&Light&

Damages!Collagen!and!Vitamin!A!

Does!not!cause!sunburn!!

!UVB&Light&

Damages!Collagen!and!Vitamin!A!

Causes!sunburn!and!skin!cancer!

Causes!pyrimidine!dimerization!!

Double!bonds!absorb!light—

melanins!dissipate!UV!as!heat!

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UVC&Light&

Damages!Collagen,!Germicidal!!

INORGANIC&NUTRIENTS&

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Vitamin&B1—THAIMIN&

Coenzyme~!thiamine!pyrophosphate—TPP!

Transfers!2!C!keto!groups!to!phosphorylated!

aldehyde!sugars!

Transketolase,&Dehydrogenases,&BCAA&DHs&

Deficiency:!Common!in!alcoholics—GI!complaints,!

weakness,!burning!feet,!peripheral!

neuropathy,!!

Beriberi—cardiovascular!and!neuromuscular!

issues,!muscle!wasting,!weakness,!high!

venous!return,!paralysis!of!eye!muscles,!

memory!loss!

WernickeOKorsakoff&Syndrome!Memory!loss!

and!mental!derangements!in!alcoholics!

Source:!pork,!grains,!nuts!!

Vitamin&B2—Riboflavin&

Precursor!to!FAD!and!FMN—electron!acceptors!

Destroyed!by!light!

Uptake!is!ATPHdependent!

Source:!Liver,!yeast,!eggs,!meat,!enriched!bread!

and!milk!

Deficiency:!Glossitis,!sore!throat,!moist!dermatitis!

of!nose!

Used!to!treat!neonatal!jaundice!

Vitamin&B3—Nicotinic&Acid&

Precursor!to!NAD+!and!NADP+!

Tryptophan!degradation!produces!small!amounts!

of!Niacin!(B1&and&B2)!

Deficiency:!Weakness,!anorexia,!indigestion,!

dermatitis,!glossitis,!mental!changes,!

mucosal!inflammation!

Source:!yeast,!liver,!fish,!legumes!

Hydrolyzed!and!absorbed!directly!in!gut!

Used!in!hyperlipidemias!

Vitamin&B6—Pyridoxine&

PLP—pyridoxal!phosphate!(prosthetic!of!

aminotransferases)!

Schiff!base!bond!on!nonHoxidative!decarboxylases!

Extracellular&lysyl&oxidase,&ALA&Synthase&of&

Heme,&glycogen&phosphorylase&

Deficiency:!Common!in!alcoholics,!peripheral!

neuropathy!

Toxicity—peripheral!neuropathy!

Sources:!liver,!fish,!mollusks,!legumes,!egg!yolk,!

yeast,!leafy!vegetables!

Vitamin&B5—Pantothenic&Acid&

Part!of!CoASH!and!Acyl!Carrier!Protein!of!Fatty!

Acid!Synthase!

PhosphorHpantetheine!attached!via!serine!

Function:!Acyl!Group!transfer!from!CoA!to!ACP!

through!malonyl&CoAOACP&Transacylase&

Essential!in!multiHenzyme!systems!with!SH!

groups;!forms!thioesters!!

Deficiency:!Not!observed!normally!

Sources:!bananas,!salmon,!whole!grains,!pork,!

dark!green!leafy!vegetables!

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Vitamin&B9—Folic&Acid&

Conjugate!of!pteridine,!pHaminobenzoic!acid!(PABA)!

and!glutamate!

Becomes!THF!through!dihydrofolate&reductase&

(NADPH)&

Pteridine,!after!Glu!and!PABA!removal,!becomes!

THB!

Folic!acid!synthesis&(Dihydropterate&synthetase)&

is!stopped!by&sulfonilamides&

THF!formation!(Dihydrofolate&Reductase)!is!

inhibited!by&methotrexate&

Homocysteine!+!MethylHTHF!!! !

Methionine!+!THF!

Deficiency!in!B12:!Folate&Trap—due!to!inability!to!

recycle!MethylHTHF!to!THF!

Deficiency:!Megaloblastic&anemia!in!pregnant!

women!on!diet!low!in!folate;!impaired!DNA!

synthesis!due!to!deficient!purines!and!dTTP!

! Neural!Tube!Defects:!Spina!Bifida,!

anencephaly!

Sources:!yeast,!liver,!kidney,!fish,!fruits,!green!leafy!

vegetables!

HEAT!LABILE!

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Vitamin&B12—Cyanocobalamin!

Two!Forms!

! Methylcobalamin!

! Adenosylcobalamin!

Homocysteine&Methyltransferase&

(homocysteine!methionine)&and&

Methylmalonyl&CoA&Mutase&

Deficiency:!Megaloblastic&Anemia!due!to!

insufficient!methylations!of!RNA,!DNA;!

Odd!FAs!in!nerve!membranes;!atrophic!

gastritis!causing!loss!of!intrinsic!factor—

Perniciuos&Anemia!

Source:!Animal!products!

Vitamin&C—Ascorbic&Acid&

Synthesized!through!glucuronate!pathway!

Reducing!Agent,!free!radical!scavenger!

Uptaken!through!Gluts!1!and!3,!Na+!transport!

Continually!recycled!through!GSH!and!NADPH!

Hydroxylation&rxns:&Dopamine!NE,&Collagen,&

homogentisate&formation,&7OαO

hydroxylase,&carnitine&synthesis,&

regeneration&of&Vitamin&E&and&iron&

reduction&in&the&gut&

Reduces!plasma!cholesterol,!CHD!risk!lowered,!

reduces!severity!of!common!cold!

Source:!Fresh!fruits,!vegetables,!sauerkraut,!red!bell!

peppers!

Deficiency:!Scurvy—dry!mouth,!eyes,!loss!of!teeth,!

decaying!gums,!petechial!hemorrhages,!poor!

wound!healing,!bleeding!from!scars,!joint!

pain!

Unstable!at!high!heat!or!neutral!pH!

Vitamin&H—Biotin!

Prosthetic!group!of!carboxylases—activates!CO2!

Pyruvate&carboxylase,&acetyl&CoA&carboxylase,&

propionylOCoA&Carboxylase,&

Methylmalonyl&CoA&Carboxylase&

Connected!to!εHNH2!of!lysyl!residue!(Schiff!Base—

carbonyl!C!bound!to!NHH)!

Deficiency:!Inducible!by!diet!that!stops!

absorption;!Avidin!binds!and!prevents!

biotin!uptake—cooking!denatures!avidin!

Proteolysis!of!biotin!enzymes!yields!biocytin;!

biotinidase!hydrolyzes!biocytin!and!

releases!biotin!for!reHuse!

Biotinidase!deficiency:!hypotonia,!seizures,!optic!

atrophy!

Source:!Intestinal!bacteria,!liver,!egg!yolks,!dark!

chocolate,!carrots,!legumes,!milk,!fish!

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WATER&SOLUBLE&VITAMINS&

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FAT&SOLUBLE&VITAMINS&

ISOPRENOIDS—REPEATS!OF!

ISOPENTENYL!PYROPHOSPHATE!

Plants!cannot!form!cholesterol!because!it!lacks!

Squaene!Synthase!to!form!lanosterol!

Plants!form!phytoenes,!lycopenes!and!βHcarotene,!

which!have!conjugated!double!bonds—light!

absorption!

Vitamin&A&

Active!Forms:!!

Retinal—prosthetic!of!rhodopsin!(rods!and!cones!in!eye—

vision)!

! Light!is!sensed!through!transformation!from!cisH!to!

transH!forms!

Opsin!senses!change!which!triggers!action!

potential!!

Deficiency:!Night!Blindness!

Retinol!

Retinoic!acid—!gene!transcription!for!maintenance!of!

epithelia!and!membranes.!Binds!to!nuclear!retinoic!

acid!receptor!(steroid!hormone!receptor);!receptor!

dimerizes!and!acts!on!Response!elements!!

Psoriasis!and!PML!Treatment!

! Deficiency:!columnar!epithelia!becomes!heavily!

keratinized!squamous!epithelia;!loss!of!mucus!

secreting!cells!from!eye!(xerophthalmia)!!

Transferred!from!plants!in!esterified!form!and!then!hydrolyzed!

by!pancreatic!enzyme!(bile&salts)!to!retinol!

Can!be!reHesterified!and!stored!in!chylomicrons!by!mucosal!cell!

then!stored!in!stellate!cells!!

Located!in!lipid!rich!areas!(liver)!

Precursor:!βHcarotene—cleaved!by!βOcarotene&dioxygenase!

then!retinal!equilibrates!with!retinol!using!NAD+/NADH!

reaction!2!retinols!

! ΒHcarotene!is!used!to!treat!Hereditary!Erythropoietic!

Porphyria!

Retinol!is!transported!in!the!blood!on!retinol&binding&protein&

Source!of!mature!Vit!A:!animal!sources:!liver,!meat,!dairy,!fish,!

orange!peel!

Source!of!provitamin!βHcarotene:!bright!fruits!and!vegetables!

Toxicity:!Teratogen;!malformation!if!doses!are!large!in!early!

pregnancy;!limb!bud!and!skeletal!development,!

vasculogenesis,!CNS!defects!

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Vitamin&D&

Deficient!in!breast!milk!

Synthesized!in!skin!in!presence!of!UVB—essential!in!

low!sun!exposure!

Active!Form:!Calcitriol!(created!through!1OαO

hydroxylase—regulatory)!

Activated&by&parathyroid&hormone,&hypocalcemia&and&

hypophosphatemia&

Calcitriol!has!lower!halfHlife!than!25Hhydroxycholecalciferol!

Calcitriol!stimulates!Ca!and!PO4!release!from!bone!(osteoclasts),!stimulates!

Ca!absorption!in!gut!(aided!by!lactose)!and!kidney!!

Parathyroid!hormone!is!stimulated!by!low!plasma!calcium!

Calcitriol!Deficiency:!Calcium!levels!will!be!maintained!from!resorption!of!

bone—Rickets&&

Vitamin!D!Toxicity:!hypercalciuria,!hypercalcemia,!metastatic!calcification!

Calcitriol!is!used!to!treat!osteoporosis!!

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Vitamin&E!

Active!Form:!αHTocopherol!

Need!more!VitE!with!increased!polyunsaturated!FA!intake!

Sources:!nuts,!seeds,!wheat!germ,!vegetable!oils,!leafy!vegetables!

Absorption!efficient!with!bile!salts;!transported!by!lipoproteins!

Used!in!reducing!free!radicals!and!quinone!intermediates!

Inhibits!PKC;!promotes!prostacyclin!release—inhibits!platelets!and!

vasodilates!

Deficiency:!Hemolytic!anemia—RBCs!sensitive!to!peroxide!(abnormal!cellular!

membranes)!

Located!in!lipid!rich!areas!(liver)!

Absorbed!easier!by!bile!salts!

Vitamin&K&

Only!Role:!PostHtranslational!carboxylation!of!Glutamate!during!synthesis!of!

prothrombin!and!clotting!factors!(No!biotin);!γHCarbon!of!glutamate!

carboxylated—strong!Ca2+!chelator;!osteocalcin!(osteoblasts)!

! Inhibited!by!dicumarol&and&warfarin!

Activated!by!Vitamin&KOdependent&carboxylase&

Deficiency:!Clotting!issues!(delayed!prothrombin!thrombin)!

Source:!Phylloquinone!from!plants,!parsley,!eggs,!meat,!dairy!

Menaquinone!synthesized!by!bacteria!in!large!intestine!

Menadione—synthetic!analog!after!enzyme!alkylation!in!body!

Not!stored—continually!turned!over!

Deficiency:!Hemorrhagic&Disease&of&the&Newborn!

Toxicity:!14!γHCarboxyglutamate!(Gla)!(coagulant)!found!in!fish,!snake!

venoms!

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INSULIN&AND&GLUCAGON& Energy&Source&Time&Frame&

Immediately:!ATP,!phosphocreatine!

Seconds!to!minutes:!phosphocreatine,!

glucose,!and!muscle!glycogen!gradually!

switching!to!liver!glycogen!

Minutes!to!1!day:!liver!glycogen,!some!

FAs!

Several!Days:!AA’s!for!gluconeogenesis!

with!gradual!switch!to!FAs!from!TAGs!

Week!to!months:!body!protein,!TAGs!and!

ketones!and!lower!metabolism!

Insulin&

Secreted&by&β&cells!and!flows!over!α!cells!to!inhibit&glucagon!

Proinsulin!undergoes!proteolytic!cleavage!(removal!of!CHpeptide)!to!produce!insulin!(active!form)!

Insulin!Release!

ATP/ADP&ratio&increased! &ATP&dependent&K+&channel&inhibited!Membrane&is&depolarized&

and&Ca2+&channels&are&activated! Intracellular&Ca2+&increases! Insulin&fuses&with&vesicles&&

GLUT!2!and!Glucokinase,!in!tandem;!act!as!the!glucose!sensor!in!pancreatic&ß&cells!because!of!its!low!

affinity!for!glucose!

! Glucokinase!has!a!Sigmoid!shape!due!to!its!high!Km!

Receptor!(CD220)!is!located!in!the!membrane!and!is!a!dimer!of!α!and!β!subunits—2!SS!bridges!

Tyrosine!Kinase!domain!that!autophosphorylates!!

IRS!is!phosphorylated!by!the!insulin!receptor!and!creates!binding!sites!for!Grb!2,!PLCγ!and!PI3HK!

Signaling!Pathway:!!

Autophosphorylation&of&receptor! &IRS&phosphorylation!PI3&and&Grb2&bind&IRS!PI3&

phosphorylates&PIO4,5OBP&to&PIO3,4,5OTP,&Grb2&activates&Ras/MAPK!PKB&and&PI&dependent&

kinase&1&(PDK1)&are&recruited&to&membrane&by&pleckstrin&homology&domains,&PLCγ&is&

activated&and&increases&glucose!PDK1&phosphorylates&and&activates&PKB&(serine&threonine&

kinase)&&

Positively&Regulated&by&Glucose&(most&potent&stimulator),&Amino&Acids&(mainly&arginine),&Neural&

Input,&Gut&hormones&and&glucagon;!Negatively&regulated&by&Epinephrine,&Exercise&

Stimulates&recruitment&of&Glut4&to&membrane&to&uptake&glucose&in&muscle&and&adipose&tissue&

Insulin&promotes&dephosphorylation&of&HOS&triacylglycerol&lipase&(indirect&inhibition)—causes&fat&

synthesis&due&to&glucose&transport&into&adipocyte,&increased&LPL&activity&

Insulin&promotes&AA&entry&into&most&cells&for&protein&synthesis&

!Glucagon&

Released!from!αHcells!of!the!pancreas!in!response!to!low&blood&glucose!

Receptor!signals!through!cAMP/!PKA!pathway!

Positively&Regulated&by&Amino&Acids,&Cortisol,&Neural&input,&Epinephrine;!Negatively&Regulated&by&

Glucose,&Insulin&and&Somatostatin!

Promotes&glucose&release&from&liver;&glycogenolysis&and&gluconeogenesis&

Release!after!a!high!protein!meal!prevents!hypoglycemia!when!AAs!enter!gluconeogenesis!

Phosphorylates!Glucokinase,!PFK2,!Pyruvate&Kinase,!Glycogen&synthase!and!glycogen&phosphorylase&

Excessive!production!may!be!caused!by!pancreatic!tumors!(glucagonoma)!

Somatostatin&

Δ!cells!in!stomach,!intestine!and!

hypothalamus!

Stops!release!of!GH!and!prevents!excessive!

energy/nutrient!investment!

Two!CNSHindependent!hormones!maintain!

homeostasis!by!monitoring!mobile!

glucose!availability!

!ProteinHrich!meals!elicit!simultaneous!

output!of!Insulin!and!Glucagon!

Lower!insulin!spike!than!glucose!

Urea!cycle!is!stimulated!with!glucagon!due!

to!amino!acids!entering!

gluconeogenesis!

!Elevated!Insulin!levels!due!to!a!high!

carbohydrate!diet!may!cause!

insulin&insensitivity!and!

decreased!populations!of!insulin!

receptors!

!Hyperproinsulinemia—incomplete!

processing!before!secretion!

Immature!forms!of!Insulin!are!

immunoreactive!(Diabetes!Mellitus!

II)!

Causes:!defective!β!cells!dysregulation!

under!sustained!glucose!

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Hypoglycemia&

Decreased!glucose!levels!promotes!release!of!insulin,!epinephrine,!glucagon,!cortisol!and!GH!

Adrenergic!Symptoms:!anxiety,!palpitation,!tremor,!sweating!

Neuroglycopenia:!headache,!confusion,!slurred!speech,!seizures,!coma,!death!

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WELL!FED!STATE!

Big&Picture:!Glucose!is!stored!as!glycogen,!proteins!and!

fat,!increased!HMP!activity!(FA!synthesis),!citrate!

shuttle!and!ATPHdependent!citrate!Lyase!

&

Liver!degrades!glucose!and!converts!products!to!fatty!

acids.!!

Break!down!of!chylomicron!remnants.!!

Fatty!acids!are!stored!in!TAGs!and!transported!

via!VLDL.!!

Amino!acids!are!taken!up!rapidly!and!synthesized!

into!proteins!

Adopose&Tissue!stores!fatty!acids!as!TAGs;!Lack!

glycerokinases—glycerophosphate!comes!from!

glycolysis:!HSHlipase,!perilipin,!pyruvate!kinase,!

and!PFK2!are!all!deHphosphorylated!and!active!

Skeletal&Muscle!converts!glucose!to!glycogen!or!to!

lactate!(during!exercise)!

! Chylomicrons!degraded!to!FAs!via!LPL!!

TAGs!deposited!

GLUTH4!activated—large!amounts!of!glucose!

enter!myocyte!

Tissue!proteins!degraded!during!postabsorptive!

period!are!resynthesized—AAs!imported!

BCAAs!are!transaminated!then!dehydrogenated!

! ! Ile!αHmethylHbutyrylHCoA!

! ! Leu!IsovalerylHCoA!

! ! Val!IsoHbutyrylHCoA!

Heart!uses!βHoxidation!to!break!down!fatty!acids!into!

usable!energy,!CO2!and!H2O!

Brain!uses!glucose!through!glycolysis!and!TCA!to!

produce!energy,!CO2!and!H2O!

! No!AAs,!FAs!or!ketones!are!consumed!

Only!glucose!can!penetrate!the!BBB!through!

GLUT3!

Pancreas:!!

For!a!carb!meal,!insulin!spike!is!high!

For!a!protein!meal,!insulin!and!glucagon!increase!

but!insulin!does!not!spike!as!high!

!

Respiratory&Quotient:&

CO2!produced/O2!consumed!

Carbs! ! 1.0!

Fat! ! 0.7!

Protein! 0.8!

ALCOHOL&

Alcohol!causes!impaired!

gluconeogenesis!sand!

hypoglycemia!

Alcohol!causes!increases!in!NADH!

NADH!blocks!pyruvate!and!OAA!

generation,!lactate!and!

malate!are!trapped!and!

cannot!be!used!in!

gluconeogenesis!

Lactic&Acidemia&

NADPH&produced&which&causes&

liver&cirrhosis&from&fat&

reduction&

ATP!output!diminished!

!

Protein&Breakdown&

Enteropeptidase!cleaves!trypsinogen!to!trypsin!

Pepsin!(active!in!low!pH—maintained!by!HCl)!

!

Pancreatic&Enzymes&of&Digestion&

Activation!via!enteropeptidase!

Produced!on!brush!border!

Enteropeptidase!removes!short!peptide!from!NH

terminus!of!trypsinogen:!trypsin!attacks!

trypsinogen!!trypsin!(cascade)!

Proteolytic!Enzymes:!Trypsin,!chymotrypsin,!

elastase:!active!at!neutral!pH!

Peptides!are!further!degraded!by!

Carboxypeptidases!A!and!B!(Zn2+!

metalloenzymes)!

!

Aminopeptidases!cleave!residues!at!NHterminus!

of!rapidly!shortening!peptide!chains!

! Free!AAs,!dipeptides—enter!cytosol,!

proceed!to!hepatic!portal!system!and!are!

metabolized!by!liver!or!released!into!

circulation!

!

Amino&Acid&Absorption&

Specific!transporters!

Concentrated!as!more!material!is!presented!

than!body!can!degrade!

Cell!decides!which!AAs!go!to!protein!synthesis!

or!other!NHrich!compounds!!

Regulation&of&Body&Weight&

Lipostatic!regulation!of!BW!

!

Leptin—From!the!adipocyte!

! Promotes!satiation,!

mimics!insulin!and!inhibits!

food!intake!

Resistin—from!adipocyte!

! Promotes!insulin!

resistance!and!food!

consumption!

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BODY!FAT!AND!OBESITY!BMI<25!is!normal!

25H30!is!overweight!

30+!is!obese!

!

!HEALTH&RISKS&

Hypertenson!

NIDDM!

Cardiovascular!Disease!

Gall!Bladder!Disease!

SexHsteroid!responsive!cancers!

Signs&of&Obesity&

BMI!and!plasma!lipids!change!point!

! BMI!increases!

! TAGS!increase!

! Cholesterol!increases!

! HDL!decreases!

Fat&Deposition&

Increases!cell!size!until!maximal!

cell!size!is!achieved,!then!mitosis!

occurs!

Fat!cells!are!not!lost.!Just!grow!in!

size!

!

Satiety!signaling—appetite!reducer!

CCK!

PYY—intestine!and!colon!

Leptin!

Insulin!

Adiponectin—from!adipocyte;!elevates!βH

oxidation!and!inhibits!lipogenesis!&!

gluconeogenesis!

Activates!AMPK—AMP!activated!ser/thr!

protein!kinase!

Increased!FA!uptake,!βoxidation!

and!glucose!uptake!

Decreased!FA!synthesis,!

gluconeogenesis!and!

glycolysis!(SYNTHETIC&

REACTIONS)!

Heterotrimer!activated!by!low!EC;!

activated!by!a!Ca2+!dependent!

phosphorylation!at!ser/thr!

!

Underfed!signals—appetite!stimulator!

Ghrelin—from!stomach;!release!of!orixogenic!

hormones!

! PraederOWilli—high!Ghrelin!levels!

!

Leptin—fatHoriginating!appetite!suppressor—

cytokine!!

White!adipose!tissue!is!the!primary!source!

More&fat!increased&Leptin!Suppressed&

appetite!

Production!is!proportional!to!fat!mass!

More!fat!causes!larger!amounts!of!nonHcarrierH

bound!!

Secretion!suppressed!by!starvation!

Action—hypothalamic!receptor!(controls!fat!

accumulation!via!control!of!appetite!&!

energy!expenditure;!increases!insulin!

sensitivity!on!liver,!muscle!and!fat!cells!

and!blocks!insulin!secretion!

Chromosome!7:!4!αHhelices!and!one!SS!bond!

!

Deficiency/receptor!defect:!Voracious!appetite,!

obesity!

Leptin!stops!fat!synthesis!and!stimulates!βH

oxidation!

!

Receptor!contains!a!phosphorylated!Tyrosine,!

cascades,!related!genes!JAK/STAT!

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STARVING&STATE&

BIG!PICTURE!OVER!TIME:!Glucose!levels!remain!relatively!constant!

due!to!gluconeogenesis!and!glycogen!usage;!metabolic!rate!falls;!

ketones!increase!causing!lower!glucose!demand;!protein!depletion!

rate!slows!down!to!preserve!function!

!

Energy!Stores—5!stages!

1. Exogenous!(dietary)!glucose!

Glucose!users:!All!tissues!

2. Glycogen,!Hepatic!Muscle!and!Gluconeogenesis!

Glucose!Users:!All!tissues!but!liver&and&WAT&&

3. Liver!Gluconeogenesis!

Glucose!Users:!All!tissues!but!liver,!muscle!and!

WAT!!

4. Liver!and!Kidney!Gluconeogenesis!

Glucose!Users:!Brain,!RBC,!renal!medulla,!less!by!

muscle!

Brain!Fuel:!Glucose!and!Ketones!1:1!

5. Hepatic!and!Renal!Gluconeogenesis!

Glucose!Users:!Brain!(lower!rates),!RBC,!renal!

medulla!

Brain!Fuel:!Glucose!and!Ketones!1:2!

Ketones!

! Steadily!rise!until!they!meet!a!maximum!plateau!

! Taken!up!by!brain,!heart!and!muscle!

Derive!from!leucine!and!lysine!and!more!predominantly!from!

βOoxidation&of&fats!

Liver:!!

! Glycogen!first!

! Gluconeogenesis!

! Ketones!from!Acetyl!CoA!from!βHoxidation!!

Adipocyte!and!Myocyte—Low!insulin—glucose!intake!suppressed!

! Lypolysis!increased—FFAs!and!glycerol!released!

Muscle!takes!up!FAs!and!ketones—Aas!sacrificed!for!

gluconeogenic!precursors!

Brain!

Ketones,!particularly!3Hhydroxybutyrate!become!more!

important!during!a!long!fast!

! Unchanged!metabolism—relative!energy!demands!greater!!

! !

! !

Kwashiorkor—semiHstarvation!

Normal!caloric!intake—diminished!protein!intake!

Decreased!serum!albumin—edema!

Combination!of!body!fat!and!edema!creates!swollen!

stomach!

Fatty!and!enlarged!liver!

Decompensation!in!secondary!infections—

inadequate!circulation/perfusion!in!infected!

tissues!

!

Marasmus—semiHstarvation!

Inadequate!intake!of!all!components&

Stunted!growth,!pronounced!weight!loss!

Loss!of!muscle!in!shoulders,!buttocks!

Hair!Loss!

Darkened!Skin!

Apathy!

Strong!resistance!to!infection!through!Antimicrobial!

peptides!(immunomodulators)!

! PotentHbroad!spectrum:!Gram!+!and!Gram!–!

! bacteria,!enveloped!viruses,!fungi,!

! cancerous!cells!

! Strongly!amphipathic—allows!partitioning!

! into!membranes!

! Unstructured!in!free!solution!and!assume!final!

! configuration!when!partitioned!into!

! membranes!

! !

! !

!

DIABETES&MELLITUS&

Direct&Causes&

Absolute!deficiency!of!insulin!!

Resistance!to!insulin!action!

TYPE&1&DIABETES&

InsulinODependent&Diabetes&Mellitus&(IDDM)&

Chronic!Hyperlycemia!

Onset!usually!during!childhood!or!puberty;!rapid!symptom!

development!due!to!insulin!secretion!below!threshold!

! Polyuria,!polydypsia!

Malnourishment!usually!

Mild!genetic!predisposition—HLAs!!

Defect:!βOcells&of&pancreas&destroyed—no!insulin!production!

Ketosis!is!common!

Insulin!is!low!or!absent!

Unresponsive!to!hypoglycemic!drugs!

Treatment:!Insulin!(hypoglycemia!possible—seizures,!intense!

sweating,!hypothermia,!coma);!stem!cell!therapy!

!

MultiHallelic!Inheritance—markedly!reduces!miscarriage!rate!

but!confers!predisposition!

! May!be!combined!with!other!infections/!disorders:!

viral!infection!that!destroys!T!lymphocytes!in!β!cells!or!

autoimmune!disorders!

MHC:!Human!Leukocyte!Antigen!(HLA)!on!chromosome&6!

contains!major!locus!for!IDDM;!chromosome&11!for!

insulin!gene!region!

! Mutation!on!HLA!modifies!antigenHbinding!regions!on!

MHC!II!which!may!cause!it!to!target!selfHantigens!on!β!

cells!!

Down!regulation!of!insulin!receptors!due!to!high!insulin!over!

time!

Lack!of!insulin!response!gives!glucagon!an!overwhelming!

influence!

! Weight!loss!!

! Ketoacidosis!

! Loss!of!muscle,!glycogen!for!gluconeogenesis!

! No!glucose!intake!into!adipocytes!or!muscle!cells!

GLUT4!

Diminished!Glucose!Tolerance—inability!to!respond!to!a!

standard!glucose!load!by!maintaining!steady!glucose!range!

!

TYPE&2&DIABETES&

NonOInsulinODependent&Diabetes&Mellitus&(NIDDM)&

Chronic!Hyperglycemia!

Onset!usually!after!35!y/o;!symptoms!develop!gradually!

Obesity!usually!present!

Strong!familial!genetic!predisposition!&!environmental!factors!

Defect:!Insulin!resistance!with!lower!insulin!secretion!

Treatment:!appropriate!care!of!body,!weight!reduction,!exercise,!hypoglycemic&

drugs,!insulin!may!be!necessary,!reduce!risk!factors!

!

Down!regulation!of!insulin!receptors!due!to!high!insulin!over!time!

Abnormally!degraded!Insulin!receptors—lowHgrade!infection!or!

inflammation!EXERCISE&REDUCES&INFLAMMATION!

! Glycated!key!enzymes!

! Defects!in!transduction!or!GLUT!function!

Hyperglycemia—No!glucose!intake!into!adipocytes!or!muscle!cells!GLUT4!

Ketoacidosis—Ketosis!from!increased!βHoxidation!is!rare!

LPL!inactive—causes!high!levels!of!chylomicrons!&VLDL!

! Hypertriglyceridemia!

Glucosuria!due!to!exceeded!renal!capacity!for!glucose!reabsorption!

! Saturation!of!glucose!transporters!in!proximal!tubules!!

! Large!loss!of!water!volume!used!to!solubilize!glucose!

! Lighter!colored!urine!with!high!density!

Osmotic!and!Dilutional!shifts!cause!muscular!weakness!and!neuromuscular!

derangements—fatigue!!

Chronic&effects—vascular!deposits!of!carbohydrateHrich!plasma!proteins!in!

basement!membrane!(glycated!collagen!on!εHlysine)!of!BVs!causing!blood!

flow!obstruction—cellular!hypertrophy!and!hyperplasia,!!

Less!pliable!arteries—high!BP!and!chance!for!stroke!and!CVD!

Cataracts!due!to!sorbitol!production!

Arethematous!lesions!due!to!higher!rates!of!plateletHderived!GF!

Vascular!insufficiency!infection!gangrene!amputations!

Diabetic!retinopathy!due!to!glycation!of!terminal!εHNH2!of!globin!

Diabetic!Neuropathy!!

Diabetic!nephropathy—End!Stage!Renal!Disease!

Mature!Onset!Diabetes!of!the!Young!(MODY)—Autosomal!Dominant!

! Genetic!and!environmental—very!strong!familial!factor!

MODY!genes!

!

!

Secondary&Causes&

Increased!secretion!of!hormone:!epinephrine!