NUTR.400.PRO.FSVIT

• Decrease Vmax
• Km stays the same

• Vmax stays the same
• Km increases

• Michaelis constant
• indicates the concentration of substrate needed to reach 1/2 Vmax
• inversely proportional to enzyme's affinity

L

• nonpolar
• polar - uncharged, acidic (low pKa), basic (high pKa)

deprotonates above this point

• leucine
• lysine

• pyruvate
• alpha ketoglutarate
• succinyl CoA
• fumarate
• oxaloacetate

• acetyl CoA (for energy metabolism or FA synthesis)
• acetoacetate (ketone body - can be used outside liver for energy production)

• E= glutamate dehydrogenase for either direction
• glutamate + NAD+ -> alpha-ketoglutarate +NH3(+NADH)
• activated by ADP (low energy), high glutamate & alpha-ketoglutarate levels
• OR
• alpha-ketoglutarate + NADPH + NH3->glutamate+ NADP+
• activated by high ammonia levels

• mechanism of creation of nonessential amino acids
• removes amino acid group (transfers ammonia/amine)
• a.a. + alpha-keto acid -> alpha-keto acid + a.a.

• amidation (glutamate -> asparganine)
• removal/addition of CH3 (glycine -> serine)
• cyclization (glutamate -> proline)
• homocysteine & serine ->cysteine
• phe -> tyr

• most tissues: glutamate + NH3 -> glutamine
• (E= glutamine synthase)
• skeletal muscle:
• transamination of pyruvate + glutamate->alanine
• (E= ALT = alanine aminotransferase)
• free NH3 is cleaved from glutamine/alanine after delivery

• free NH3 + CO2 + 2 ATP from mitochondria
• + Asparate's NH3 in cytosol
• (asprartate from AST acting on glutamate + oxaloacetate)
• = urea (cleaved from arganine) - diffuses from liver to blood - excreted by kidneys & a small amount in feces

• porphyrins (that bind metal ions - FE++) including heme
• catecholamines
• -dopamine & norepinephrine - neurotransmitters
• -norepinephrine & epinephrine - hormones
• histamine
• serotonin
• phosphocreatine - energy storage in muscle
• melanin
• carnitine - line between protein & fat metabolism

• met is precursor of SAM
• universal methyl group donor
• met resynthesized using methyl group from N5MTHF
• this creates homocysteine- associated with CVD
• homocysteine is converted to cysteine by serine & B 6,9,12

• covalent peptide bond - usually in trans configuration
• no free rotation
• carboxyl - amino

• formed by H bonds
• alpha helix
• B pleated sheet
• can be arranged in parallel or antiparallel configuration
• nonpolar groups found in phospholipid bilayer
• ex. barrel - channel

• > 200 aas
• disulfide (covalent) bonds
• ionic interactions
• H bonds
• hydrophobic interactions
• low energy state
• begins folding during synthesis w/ help of cheperones
• enhances solubility in water

unfolding of secondary & tertiary structures

• 2 or more polypeptide chains
• ionic bonds, H bonds, hydrophobic interactions

• complex of protoporphyrin IX & Fe3+
• can support redox catalysts, electron transport (cytochromes in ETC), oxygen transport (hemoglobin, myoglobin)

• in heart & skeletal muscle
• reservoir & carrier for O2 within myocyte
• transports O2 to the mitochondria for ETC
• O2 release is stimulated by buildup of CO2 & lactate
• single polypeptide folded into 8 stretches of alpha-helix (A-H)
• heme group in between helix E & F

• 2 alpha & 2 beta chains w/ helical structure
• can hold 4 O2s
• cooperativity
• ALLOSTERIC EFFECTS
• T(tense) form release O2 - once 1 becomes tense, the rest become more tense
• low pH (from lactic acid) & high pCO2 - lower affinity
• 2,3 bisphosphoglycerate increases as O2 levels decrease, so 2,3 BPG causes less affinity for O2 (good normally) - response to hypoxia or chronic anemia(not good)

• R form has high affinity for O2 - increases as each group binds
• high pH &low pCO2 - higher affinity for O2

• triple helix
• lots of proline & glycine (every 3rd aa is gly)
• tropocollagen -> disulfide bridges must be cleaved to form collagen

• fibrous protein
• tropoelastin-> elastin + glycoprotein microfibrils = elastin
• (alveoli, artery walls, elastic ligaments)

inorganic metal ion

• organic, covalently bound to enzyme
• ex. vitamin
• phosphate
• biotin

organic with transient interactions with enzyme

inactive enzyme (w/o non-protein groups bound)

active enzyme (w/ non-protein component(s))

• Michaelis-Menten kinetics
• (as opposed to allosteric w/ sigmoidal curve)

• substrate concentration
• temperature
• pH

• allosteric - (effectors) bind noncovalently - homotropic (substrate is usually activitor) vs. heterotropic (component other than substrate activates or inhibits)
• covalent modification - phosphorylation (protein kinases), dephosphorylation (phosphatases)
• induction & repression - by modulation of gene transcription

• acid hydrolases (endocytosis)
• ubiquitin-proteasome mechanism - tagged w/ ubiquinin (ubiquinitation), cytosolic, barrel-shaped proteosome recognizes, proteases of proteosome cleave to short polypeptide fragments then aas, ubiquitin is recycled

• HCl - denatures
• pepsinogen -> pepsin - cleave to polypeptides & aas

• zymogens -(activated by trypsin)-> proteases
• enteropeptidase activates trypsinogen->trypsin - Arg, Lys
• chymotrypsin - Leu, Met, Trp, Tyr, Phe
• pro--->elastase - Gly, Ala, Ser
• pro---->carboxypeptidase A - Val, Ala, Iso, Leu (nonpolar)
• pro---->carboxypeptidase B - Arg, Lys

• EXOPEPTIDASES:
• aminopeptidases - cleave N-terminal residue from oligopeptides
• tri & dipeptidases

• free aas absorbed by Na+ dependent transporter
• di & tri peptides by H+ linked transporter - then get hydrolyzed inside enterocytes

• proximal tubule can't reabsorb COAL (cystine, ala, ornithine, and lys) (works wih Na/K pump)
• precipitation of stones

• phenylketonuria
• mutation in phe hydroxylase gene or tetrhydrobiopterin
• phe accumulates - retardation, odor
• lack tyr - hypopigmentation

• maple syrup urine disease
• deficiency in branched-chain alpha keto acid dehydrogenase (which breaks down leu, iso, val)
• toxic to brain

defect in tyr metabolism

• high levels of homocystine & met in plasma & urine
• low levels of cystine in plasma & urine
• premature arterial disease due to oxidative damage, inflammation, endothelial dysfunction
• restrict met intake
• supplement w/ B6, B12 & folate (B9)

• decreased capacity of urea cycle caused by liver disease or genetic deficiency
• neurotoxic
• low protein diet, drugs that bind AAs

• defect in heme synthesis
• skin eruptions

• deposition of bilirubin in skin (product of heme degredation)
• hemolytic - associated w/ anemia - can't be excreted from gut quick enough
• hepatocellular - damaged liver
• obstructive - of bile duct
• neonatal - bilirubin glucuronyltransferase low at birth

• 1. amyloidoses - amyloid (B-pleated sheet) accumulation - neurotoxic- Alzheimers
• 2. prion disease - infectious form of protein (PrP/prion) is an altered version of the normal form (normal has a-helices & PrP has b-pleated sheets)

• deficiency of elastase
• w/out it, immune cells can't get through tight junctions

• retinol & retinal (reversible rxn)
• formation of retinoic acid (CO-OH) by oxidation of retinol is irreversible

• some carotenoids - cooking makes them easier to absorb
• beta carotene - makes 2 retinal --> retinols, but less bioavailable (9-22% absorption)
• alpha carotene
• cryptoxantin - oranges/tangerines
• (lycopene, lutein, & zeaxathin have no Vitamin A activity, but are antioxidants)

E & C

B

A - retinal

K

D & K

Vitamin E

Vitamin A

Vitamin D

• Vitamin K
• phylloquinone - K1-plant sources - major source/ most biologicallly active
• menaquinones-K2 - animal sources & gut
• menadione - K3 - synthetic

Vitamin E

• retinol is reesterified & secreted in chylomicrons & lymph
• taken up by liver
• RBP, retinol-binding protein, transports retinyl esters to extrahepatic tissues where they attach to specific receptors
• cellular RBP carries retinol in cytosol

• rentinoic acid binds to retinoic acid receptor (RAR) in nucleus
• RA-RAR complex is a transcription factor that interacts with retinoic acid response elements (RAREs)
• transcription of genes that function in:
• embryonic development (essential for spermatogenesis & preventing fetal resorption)
• cell proliferation
• cell differentiation - ex. epithelial goblet cells (lack of vitamin A leads to dry mucous membranes, prone to infection)
• immune functions (epithelial cell growth & T lymphocytes)
• bone growth

Retinoic Acid

retinol transported to retina --> cis-retinal + opsin --> rhodopsin + light --> trans-retinal + nerve impulse

trans-retinal recycled by conversion to trans-retinol then cis-retinol then trans-retinal

• amount of rhodopsin increases in dim light as more cis-retinal binds to opsin
• rhodopsin is broken down when light is turned on
• depends on amount of Vitamin A that is available - not alot, then can't adjust quickly to bright or dark

iodopsin, violet pigment

• dry, pruritic skin
• enlarged & cirrhotic liver
• rise in intercranial pressure in the brain
• congenital malformations

• trans retinoic acid improves survival for acute promyelocytic leukemia where there is translocation between genes that normally help WBCs mature
• this is because RA receptor gene is affected by translocation

• D2 - ergocalciferol - plants
• D3 - cholecaciferol - animals

• 1. Skin: UV rays convert 7-dehydrocholesterol to cholecalciferol (D3)
• 2. Liver: D3 is hydroxylated to calcidiol (predominant form in plasma & storage form in liver) - requires NADPH
• 3. Kidney: Calcidiol is hydroxylated to calcitriol - requires NADPH

activated by low plasma phophate or low Ca2+

• BINDS TO VITAMIN D RECEPTOR FORMING CALCITRIOL VDR COMPLEX
• THIS BINDS TO VDREs to promote mineral metabolism, immune response, cancer regulation...
• maintaining homeostasis through transcription regulation
• bones/teeth
• blood clotting/wound healing
• nerve transmission that controls blood pressure
• macronutrient energy metabolism (gluconeogenesis)
• membrane transport
• muscle contraction

• stimulated by calcitriol by increasing binding of Ca2+ to calmodulin & increasing sythesis of calbindin & Ca2+ ATPase
• lumen - through Ca channel - binds to calmodulin then to calbindin then leaves enterocyte through Ca2+ATPase

• PTH stimulates kidneys to produce more calcitriol from calcidiol - which increases intestinal absorption, proximal tubule reabsorption (by increasing transcription of transporters), and stimulates resorption of bone by activating osteoclases
• PTH stimulates osteoclasts
• PTH signal kidneys to slow Ca2+ excretion, but increase phosphate excretion

• PTH in the blood drops
• Kidneys produce little/no calcitriol
• synthesis of Ca2+ transporters in small intesting & kidney decrease
• calcitonin secretion from thyroid gland is increased, inhibiting osteoclasts & acvating osteoblasts to use blood Ca2+ to mineralize bone

• low absorption of dietary Ca2+ due to vitamin D deficiency
• skeletal deformities due to incomplete mineralization resulting in soft, pliable bones
• adult form = osteomalacia - often seen in individuals with diseases of organs involving vitamin D production / absorption
• mutations in VDR gene or 25-hydroxy-cholecalciferol 1-hydroxylase gene
• renal rickets - calcitriol can be administered

• low blood Ca2+ levels
• high phosphate levels - PTH stimulates phosphate secretion
• treatments = vitamin D + PTH

• UL = 100 mcg = 4000IU
• hypercalcemia
• Ca2+ deposits in soft tissues (heart, lungs). blood vessels
• CNS (loss of appetite, nausea...)
• loss of bone mass - unbalanced bone resorption = decalcification

• posttranslational modification - carboxylation
• blood coagulation, bone mineralization, cell growth & proliferation
• cofactor for v-gluamyl carboxylase that catalyzes carboxylation of glutamic acid residues -> v-carboxyglutamic acid (Gla)
• Gla domains have high affinity for Ca2+

• glutamate is carboxylated with the help of vitamin K to form Gla with Ca2+ attached
• the oxidized vitamin K then needs to be recycled by epoxide reductase & NADH to form its reduced form
• short half life

• warfarin- inhibits epoxide reductase from reducing/recycling vitamin K
• dicumarol from sweet clover also inhibits clotting

• it aids in carboxylation forming Gla in the precursors that form mature clotting factors II, VII, IX, and X leading to fibrin
• prethrombin -> prothrombin (+ thromboplastin from intrinsic or extrinsic pathway) -> thrombin ->which turns fibrinogen into fibrin
• prothrombin-Ca2+ complex weakly binds to phospholipids on platelets which increases the rate of proteolytic conversion of prothrombin to thrombin
• Ca2+ provides binding opportunity & it is there because vitamin K carboxylated precursors forming the Gla

• assists with formation of Gla residues enhancing Ca2+ binding capacity of osteocalcin which is secreted by osteoblasts for bone mineralization
• plus at least 2 other bone proteins require vitamin K for carboxylation

• Gas6
• found in nervous system, heart, lungs, stomach, kidneys & cartilage
• cell-signaling, cell adhesion, proliferation, protection agains apoptosis, platelet signaling

• rare, but is possible with fat malabsorption and extended antiobiotic use
• prothrombinemia is a side effect - nosebleeds, gums bleed, blood in urine & stool
• decreased bone density
• newborns get vitamin K injection for protection from brain hemorrhage
• mega doses of vitamin A hamper intestinal absorption
• mega doses of vitamin E block K-depended clotting factors

• rare - body excretes it rapidly
• hemolytic anemia, esp in newborns

• tocopherols (alpha, beta, gamma, & delta) - saturated
• tocotrionols (alpha, beta, gamma, & delta) - unsaturated
• 90% is stored in adipose
• 10% in plasma membranes

• antioxidant
• stabilization of cell membranes
• pollution oxidative damage protection in lungs
• DNA/cancer
• protect against peroxidation / CVD
• protection of liver, breast, muscle, mainenance of B-carotene

• alpha tocopherol prevents free radical damage to PUFA in cell membranes
• PUFAs are susceptible to peroxidation
• forms a stable free radical
• tocopherol accepts electron stabilizing free radical - recycled by ascorbic acid - recycled by GSH - recycled by NADPH

• very rare - premature infants / fat-malabsorption syndromes
• hemolytic anemia - insufficient protection of RBCs
• cataracts - oxidation in lense of eye
• CVD
• decline in immune function

• least toxic fat soluble vitamin
• high doses counter vitamin K's blood clotting mechanism