Metabolism - Exam #2, Part 1 Flashcards
1
Q
Who discovered the first VITAMIN in the early 20th century?
A
- Casimer Funk;
- From rice polishings and was an anti beriberi substance;
- “Vitamine” = amine vital for life
2
Q
Why was the name changed to just Vitamin?
A
- “Vita” means “life” in Latin;
- But found that only a few substances were actually amines
3
Q
What was the main reason for the discovery of Vitamins?
A
- Because of their ABSENCE in diets of animals and people;
- Found due symptoms that developed from DEFICIENCIES!!;
- Today more is known about deficiency than sufficiency for optimal health
4
Q
What is the key focus of Interactions?
A
- Think more about what the vitamin DOES than what happens if it is deficient;
- Sometimes difficult to relate function to deficiency;
- Focus now should be on OPTIMAL HEALTH, not just avoiding deficiency
5
Q
How were the chemical structures/ of Vitamins discovered?
A
- Isolation and synthesis;
- Each was then given a name of a single substance, but it was discovered that vitamins may have a VARIETY of FUNCTIONS
6
Q
What are Vitamers?
A
- Vitamin activity may be found in several closely related compounds;
- One or more related chemical substances that fulfill the same specific vitamin function;
- EX: Vitamin A with retinol, retinal, and retinoic acid that can have different functions
7
Q
What are Vitamins?
A
- Organic compounds with regulatory functions;
- Essential nutrients that cannot be synthesized or not in adequate amounts;
- Not chemically related to each other;
- Fat-Soluble = A, D, E, K;
- Water Soluble = Vit. C and B-Vits
8
Q
How do Fat-Soluble Vitamins travel in the body?
A
- Fat-soluble vitamins bypass the liver like fats;
- Travel through the Lymph
9
Q
How do Water-Soluble Vitamins travel in the body?
A
- Water-soluble vitamins are abosorbed into the portal blood through the portal vein from the GI tract;
- They are NOT STORED except in a pool of cell in their binding enzymes and transport proteins and excesses excreted in urine;
- But, B12 can remain for long periods
10
Q
How are the recommendations for vitamins provided?
A
- Established EARs from biological markers and then derived RDAs;
- When insufficient data for EAR, AI is provided based on observation
11
Q
What is Vitamin C?
A
- 6-carbon compound;
- L-isomer is ACTIVE:
- NOT called vit. C in mammals, but ASCORBIC ACID or ASCORBATE
12
Q
What causes the human inability to synthesize Vitamin C?
A
- Lack of the last enzyme in the synthetic pathway = Glucolactone oxidase;
- Also, Primates, fruit bats, guinea pigs, and some birds cannot SYNTHESIZE the L-ascorbic acid
13
Q
What is Scurvy?
A
- Vitamin C deficiency disease;
- Body pools below 300 mg and plasma vitamin C below 0.2 mg/dl;
- “spitting out teeth below ship’s deck”;
- Fatal if untreated;
- Can be prevented with intakes as little as 10mg Vit. C per day = RARE to develop
- Symptoms are due to compromised COLLAGEN structure which causes weakening of blood vessels, connective tissues and bone
14
Q
When was Vitamin C discovered?
A
-Isolated in 1928 and its structure determined in 1933;
-Szent-Györgyi (1928) and King (1932) are both given credit for the co-discovery;
Haworth determined its structure
-Szent-Györgyi and Haworth won Nobel prize in 1937
15
Q
What are the food sources of Vitamin C?
A
- Present in many fruits & vegetables;
- CITRUS products most often given credit as the best source
16
Q
What are the types of Vitamin C supplements?
A
- Free ascorbic acid;
- Calcium ascorbate;
- Sodium ascorbate;
- Ascorbyl palmitate;
- Often see rose hips (seed capsule on roses) on labels of vitamin C supplements
17
Q
What DIGESTION of Vitamin C takes place?
A
-NO DIGESTION required for absorption into intestinal cells
18
Q
How is Vitamin C absorbed?
A
- Absorption by SVCT1 (higher capacity) & SVCT2 that are sodium co-transporters
- Sodium-dependent Vitamin C Transporter;
- REDUCTION prior to absorption so absorbed as ascorbate by SVCTs
19
Q
How is the OXIDIZED form of Vitamin C absorbed?
A
- Dehydroascorbate absorbed via GLUT1 and GLUT3 transporters;
- Dehydroascorbate is converted in intestinal and other cells to ASCORBATE;
- Tissue Cells have SCVT1 for ascorbate
- SVCT2 present in most tissues except skeletal muscle and lungs
20
Q
What cells lack the SVCT2 for Vitamin C?
A
- Red blood cells;
- Los SVCT proteins during maturation;
- “SVCT2 knockout” animals genetically engineered to lack this functional gene, die shortly after birth, suggesting that SVCT2-mediated vitamin C transport is necessary for life
21
Q
What is the absorption rate for Vitamin C?
A
-Usual intakes are 30-180 mg/day and absorbed at 70 to 90%, respectively;
-ABSORPTION decreases with higher intakes =
16% at intakes ~12 g vs. 98% at low intakes < 20 mg
22
Q
What is the main regulator for Vitamin C absorption?
A
- Intake!!;
- At HIGH intakes will absorb much less because the excess not needed by the body will be excreted;
- Water-soluble vitamins are not stored!;
- At LOW intakes absorption will be very high so they body will utilize ALL that is consumed
23
Q
When does Simple Diffusion of Vitamin C occur?
A
- At high amounts of vitamin C throughout stomach and small intestine → Occurs through anion channels
- Diffuses through anionic channels into blood and exists as FREE vitamin in blood
24
Q
Where is the greatest concentration of Vitamin C?
A
- Tissues have GREATER amounts than blood;
- Maximal vitamin C pool is 2g
- Highest concentrations in ADRENAL and PITUITARY GLANDS
- High levels also in white blood cells, eyes and brain;
- Assume in free form in tissues and compartmentalized for reactions
25
What is needed to achieve the Maximized Body Pool for Vitamin C?
- Estimated need 100 to 200 mg ingestion of vitamin C per day;
- Gives a plasma concentration of 1.0 mg/dl
26
What is the mechanism for the interconversion of ascorbic acid and dehydroascorbic acid?
- During oxidation of ascorbic acid, free radical ascorbyl radical forms, but has a short half-life;
- Oxidation of the radical forms of Vitamin C occurs;
- Dehydroascorbic acid can be reduced to ascorbic acid with hydrogens provided by reduced Glutathione (GSH)
27
What is Glutathione?
- Antioxidant that prevents free radicals;
| - Tripeptide of Cysteine, Glutamate, and Glycine
28
What reactions require Vitamin C (Ascorbate)?
[Functions in a number of Hydroxylation Reactions]
- Collagen synthesis
- Carnitine synthesis
- Tyrosine synthesis and catabolism
- Neurotransmitter synthesis
29
What are the main COFACTORS that Vitamin C acts on?
-COPPER or IRON cofactor;
30
What is the role of vitamin C in these reactions?
- ANTIOXIDANT;
- Cofactor loses and electron and becomes oxidized to allow the enzymatic reaction to occur → ;Cu3+ → Cu2+] [Fe3+ → Fe2+];
- OXIDIZED form is a damaging FREE RADICAL
- Vitamin C resupplies the lost reaction to reduce the cofactor for function in future reactions and prevention of radicals = becomes OXIDIZED
- Vitamin C keeps the cofactor in the reduced state so the enzyme can function;
- Cofactor GAINs electrons and is no longer damaging
31
What other components can Vitamin C REDUCE?
- Tyrosine synthesis & catabolism;
- Neurotransmitter synthesis (Norepinephrine, Serotonin, Other peptide hormones)
- Collagen synthesis
- Carnitine synthesis
32
How is Phenylalanine converted to Tyrosine with the help of Vitamin C?
Vitamin C (ascorbate) functions as the reducing agent (BECOMES oxidized) =
- Converts oxidize Copper atoms (Cu2+) to reduced Cu3+ AND;
- Converts oxidized iron (Fe2+) to reduced Fe3+
33
What is Alkaptonuria?
- Defects in the enzyme Homogentistate dioxygenase = involved in Phenyalanine to Tyrosine metabolism involving Vitamin C;
- Leads to accumulation of homogentisate in the body with painful joints and secretion of it in urine and the compound turns black with exposure to air
34
Defects in what enzyme cause PKU?[
| Phenylalanine to Tyrosine metabolism]
Phenylalanine monooxygenase -Fe
35
Defect in what enzyme cause Tyrosinemia type II?
| [Phenylalanine to Tyrosine metabolism]
Aminotransferase-PLP
36
What is Amidation of peptides?
- ADDITION of an amide group to the end of a polypeptide chain =
- In a first reaction step the GLYCINE is oxidized to form alpha-hydroxy-glycine;
- The oxidized glycine cleaves into the C-terminally amidated peptide and an N-glyoxylated peptide (Glyoxylate);
- C-terminal amidation is essential to the biological activity of many neuropeptides and hormones
37
What is Vitamin C's role if Amidation of peptides with C-terminal Glycine?
- Converts the oxidized copper and back to its reduced form Cu1+;
- Ascorbate (Vit C) oxidized back to Dehydroascorbate = LOST an electron
38
What are some of the neurotransmitters that require Vitamin C for synthesis through AMIDATION?
- Bombesin (gastrin-releasing peptide [GRP];
- Calcitonin;
- Cholecystokinin (CCK);
- Thyrotropin;
- Corticotropin-releasing factor;
- Oxytocin;
- Vasopressin
39
What is Collagen?
Structural protein in skin, bones, tendons, cartilage, dentine, basement membrane lining capillaries, and maintenance of scar tissue;
-Mammals typically have more than 30 variants each with a different structure and function
40
How are the molecules of collagen cross-linked together?
- Vitamin C-dependent hydroxylations of proline and lysine occur post-translationally after amino acid is in the protein forming the TRIPLE HELIX;
- Hydroxylation adds an (-OH) into the molecule to form a new bond;
41
What are Dioxygenases?
–Enzyme which catalyzes the incorporation of both atoms of molecular oxygen into substrates using a variety of reaction mechanisms
42
What are the specific dioxygenase amino acids of Collagen?
-Two proline hydroxylases (prolyl 4-hydroxylase and prolyl 3-hydroxylase) that are dioxygenases;
-A lysine hydroxylase (lysyl hydroxylase) that is also a dioxygenase
= These hydroxylated amino acids provide more STRENGTH to the collagen
43
What copper dependent enzyme can also promote collagen cross-linking?
-LYSYL OXIDASE can oxidize the lysine and hydroxylysyl residues to promote cross-linking
44
How does Vitamin C facilitate collagen cross-linking?
- Ascorbate (Vit. C) converts the oxidized IRON bac to reduced Fe3+ in the enzymes Lysyl hydroxylase and propyl hydroxylate;
- TWO atoms of dioxygen are REDUCED to ONE HYDROXYL group and one H2O molecule by the concomitant (following) oxidation of NAD(P)H;
- The enzymes add ONE atom of Oxygen in the hydroxyl group of the product and the other in Succinate
45
What are Monooxygenases?
-Enzymes that incorporate ONE hydroxyl group into substrates in many metabolic pathways
46
What are the genetic defects that can occur in collagen structure?
-Osteogenesis imperfecta is abnormal bone formation in babies
-Ehlers-Danlos syndrome is characterized by loose joints
= Replacement of a single GLYCINE by larger amino acids in a different location for each disorder → Glycine is the SMALLEST AA;
-Both can be lethal
47
What is the triple coil of collagen composed of?
- 3 distinct alpha-chains;
| - Alpha-chains are NOT alpha-helix, and the structure is very different
48
Differences in Alpha HELIX and Alpha CHAINS
- Alpha HELIX is RIGHT handed, but the Alpha CHAINS are LEFT handed
- Alpha helix has 3.6 amino acids per turn
- Alpha chain has 3 amino acids per turn
49
How is collagen coiled?
- Triple helix of 3 alpha-chains is a coiled coil and is considered a super-helical structure as the three chains are super-twisted about each other in a RIGHT handed coil;
- Opposite in sense to the left handed helix of the α chains;
- LEFT handed alpha-chains make up the full RIGHT handed SUPER-COIL
50
What is Carnitine?
- Non-protein nitrogen-containing compound;
- Involved with transport of long-chain fatty acids into mitochondria for β-oxidation;
- Made from LYSINE that has been methylated by S-adenosylmethionine =;
- Vitamin C reduces the Iron in the process
51
What other reactions might require vitamin C?
-Microsomal metabolism;
-In the Reticuloendothelial System, also called Macrophage System
= Include hydroxylation reactions that are catalyzed by monooxygenases that require reducing agents and vitamin C may play a role
52
What are microsomes?
- in the smooth ER membranes;
| - Degrade hormones, modulate cholesterol, degrade xenobiotics (drugs, carcinogens, additives, pollutants, etc)
53
What is the Reticuloenothelial or Macrophage System?
- Body's defense mechanism;
- Phagocytic cells that destroy bacteria, foreign substances, and worn out/abnormal body cells;
- Derived from precursors in the bone marrow;
- Become monocytes in the bloodstream or enter tissues and become macrophages
54
What is an Antioxidant?
- Vit. C can be a generic antioxidant in aqueous solution (blood, in cells);
- Prevents oxidation of other molecules (Leads to free radicals) by REDUCING them;
- Can REDUCE other reducing agents when they are oxidized and vice-versa;
- Once used, most tissues have REDUCTASE to reform ascorbate
55
What other Reducing Agents can Vitamin C reduce?
- It can REDUCE vitamin E at the aqueous:lipid interface;
| - It can REDUCE free radicals and reactive species before they damage DNA, PUFA, phospholipids and proteins in cells
56
Does Vitamin C show any Pro-Oxidant activity?
- Pro-oxidant only IN VITRO (lab) and at very high non-physiological concentrations;
- Used to think high doses released iron stores leading to oxidation, but now state no.
57
In what other system might Vitamin C play a role?
- Collagen gene expression;
- Synthesis of bone matrix, proteoglycans, and elastin;
- Regulation of cellular nucleotide (cAMP and cGMP) concentrations
- Immune functions, including complement synthesis
58
What is the relationship between Vitamin C and colds?
- High doses NO effect in most studies, but a few studies show a decrease in duration of symptoms;
- Does enhance many immune cell functions and destroys HISTAMINE that causes many of a cold’s symptoms
59
What is the relationship between Vitamin C and cancer?
- Makes sense that antioxidant would prevent cancer;
- Some epidemiological studies indicate protection against cancers of the oral cavity, pharynx, esophagus and stomach;
- Fruit and vegetable consumption is correlated with reduced cancers;
- But a lot of studies show no effect
60
What is the relationship between Vitamin C and CVD?
- Epidemiological studies with fruits and vegetables and vitamin C suggest a protective;
- Intervention studies with vitamin C and other antioxidants DO NOT support the epidemiological studies;
- Megadose supplements of antioxidants INCREASE mortality and morbidity risks
61
What is the relationship between Vitamin C and eye health?
-Studies show benefit against cataracts and age-related macular degeneration with consumption of mutivitamin
62
What is the INTERACTION between Vitamin C and Iron?
-Enhances non-heme iron absorption
63
How much accumulation of ascorbate (vit. C) occurs within the body?
- Dietary doses;
| - Until the plasma levels reach the renal resorption threshold, which is about 1.5 mg/dL in men and 1.3 mg/dL in women
64
What happens once Ascorbate concentrations in the plasma exceed the renal absorption threshold?
- Point of body saturation;
- Rapidly excreted in the urine with a half-life of about 30 minutes;
- At intakes about 500 mg, ALL vitamin C is usually excreted (assume above renal threshold)
65
What happens when Ascorbate concentrations in the plasma are below the threshold?
- Actively retained by the kidneys;
- Excretion half-life for the remainder of the vitamin C store in the body thus INCREASES greatly, with the half-life lengthening as the body stores are depleted;
- Half-life rises until it is as long as 83 days by the onset of the first symptoms of Scurvy.
66
What are the other Urinary metabolites that accompany Vitamin C excretion?
- 2-O-methyl-ascorbate, ascorbate-2-sulfate, and 2-ketoascorbitol;
- Excreted as CO2 and water
67
What is the RDA (bio marker) for Vitamin C?
- Men = 90 mg
- Women = 75 mg
- Pregnancy = 100 mg; Lactation = 120 mg;
- + 35 mg for SMOKERS and this was first recognized as a greater need in 1989 RDA → Increased RDA due to the extra oxidative stress from cigarette smoking toxins and thus generally have lower blood levels of Vit. C
68
What is the RDA for Vitamin C based upon?
-Nearly maximizing tissue concentrations and minimizing urinary excretion of the vitamin;
Amount needed to maintain NEUTROPHIL saturation (AKA White Blood Cells) with minimal urinary excretion;
-Some in the past before the year 2000 have argued for an RDA of 200 mg/day as that would be the amount would consume if met the recommendation for fruits and vegetables
69
What is the UL and toxicity for Vitamin C?
- 2 g, based on osmotic diarrhea (metabolized by bacteria) and GI pain;
- Rebound scurvy not substantiated;
- Excess in urine can interfere with urine glucose test, interfere with detection of blood in urine and feces
- People prone to a couple of types of kidney stones should avoid large doses of vitamin C
70
How do Plasma and Serum Concentrations indicate Vit. C nutritional status?
- Concentrations respond to changes in dietary intake and most convenient assay;
- Quick and easy indicator; daily lab use and diagnosis
71
How do White Blood Cells indicate Vit. C nutritional status?
- Better reflect body stores, but assay more difficult for routine use;
- More indicative, but also too difficult for immediate, general diagnosis
72
When is there a Vitamin C deficiency?
- DEFICIENT = <0.2 mg/dl, tissue saturation 1.0 mg/dl
| - Recommended intakes result in a range of 0.6 to 0.8 mg/dl
73
What is Thiamin?
- First B vitamin identified;
| - B1
74
What is BeriBeri?
| "Weakness"
- Thiamine deficiency disease present for over 1000 years in East Asia occurred where white rice was the staple of the diet;
- Thought to be an infectious disease until determined chickens fed white polished rice developed the disease and got better when fed brown rice;
- Polished rice is essentially just starch
75
Who were the scientists that discovered Thiamin?
- NEED by Dutchman C. Eijkman (1800s) -- Discovered that chickens fed a diet consisting of polished (removal of outer layer) rice developed neuorlogical problems;
- ISOLATED from RICE BRAN in 1912 by Casmir Funk
- STRUCTURE by R. Williams about the mid 1930s
76
What are the food sources of Thiamin?
- Enriched grains, whole grains, legumes, nuts and seeds;
- Found in yeast, wheat germ and soy milk;
- In food is sensitive to heat, oxygen and low-acid conditions (stable in acid and unstable in alkaline)
77
What are the ANTI-Thiamine enzyme or binding factors in foods?
- In raw seafood (cooking destroys);
| - Binding factors block absorption = Polyhydroxyphenols
78
How do Polyhydroxyphenols block Thiamin?
- Tannic and caffeic acid are thermostable and INACTIVATE thiamin by OXIDATION;
- Reducing compounds protect from oxidation
- Divalent minerals accelerate oxidation (valence of two and can form two bonds)
79
What constitutes the structure of Thiamin?
-Pyrimidine ring +
-Thiazole ring
(Linked with a Methylene bridge)
80
What are the forms of Thiamin found in FOOD?
- Plants = NONPHSOPHORYLATED or free form;
| - Animals = PHOSPHORYLATED primarily as thiamin diphosphate (TDP) in mucosal cells; AKA: Thiamine Pyrophosphate (TPP)
81
What are the forms of Thiamin supplements?
- Thiamin hydrochloride or
| - Thiamin mononitrate
82
What is happens to Thiamin initially for absorption?
- Intestinal PHOSPHATASES hydrolyze the phosphate off the thiamin PRIOR to absorption;
- Removal of –PO4 allows for absorption;
- Primarily in the JEJUNUM with small amounts absorbed in the other two small intestine sections as free thiamin (FREE thiamine is simply absorbed)
83
How is Thiamin absorbed depending on concentration?
- High dietary levels = absorbed by diffusion;
- Low dietary levels = absorption is active and involves sodium-dependent carriers;
- But may not involve sodium, but rather hydrogen ion antiport (EXCHANGE thiamine for H+)
84
What are the Thiamin carriers?
ThTr1 & ThTr2;
- Defects in gene for ThTr1 results in thiamin DEFICIENCY;
- BUT ThTr2 “picks up the slack” with ThTr1 KO mice;
- Both of these saturable and in many tissues
85
How is Thiamin actively transported to the blood?
- Crosses basolateral membrane into blood via active transport by hydrogen antiport;
- Ethanol (alcohol) interferes with this active transport into the blood;
- Alcohol inhibits the expression of ThThr1 and ThTr2 and therefore inhibits Thiamin absorption
86
What is the form of most BLOOD thiamin?
- PLASMA has free thiamin, bound to albumin, or TMP;
- ~90% of blood thiamin is WITHIN blood CELLS as TDP (or TPP), which was formed within the cell, with smaller amounts of TMP;
- Transport into red blood cells by FACILITATED DIFFUSION as FREE thiamin bound to Albumin or TMP = only fonts that can enter cels
- (into OTHER tissues requires energy);
87
How much Thiamin is found within the body?
~30 mg of Thiamin;
- Small concentrations stored in liver, muscles, heart, kidneys and brain;
- Muscles contain about HALF the body’s thiamin; -Thiamin half-life = 10-20 days
88
What is the MAIN form of Thiamin found within the human body?
- ~80% of thiamin in body is TDP (TPP) = Thiamin Pyrophosphate;
- Several interconvertible forms = free, TMP, TDP (TPP), and TTP;
- ~10% in the body tissues as TTP
89
What happens to Thiamin when it is absorbed into the Portal blood?
-After absorption into PORTAL blood, thiamin is taken up by the LIVER and converted to its TDP COENZYME form
90
What are the 3 main functions of Thiamin?
1. Energy transformation (coenzyme);
2. Synthesis of pentoses and nicotinamide adenine dinucleotide phosphate (NADPH) (coenzyme);
3. Nerve conduction (NOT a coenzyme role)
91
What is the Coenzyme form of Thiamin?
-TDP (or TPP);
Plays key role in oxidative decarboxylation reactions (SAME MECH.):
-Pyruvate to acetyl CoA
-α-ketoglutarate to succinyl CoA
-Conversion of the three branched-chain amino acids isoleucine, leucine and valine
92
How does TPP work as a coenzyme in these reactions?
-TPP catalyses the reversible cleavage of a substrate compound at a carbon-carbon bond connecting a carbonyl group to an adjacent reactive group (usually a carboxylic acid or an alcohol)
93
Steps of the TPP Mechanism
1. Reactive carbon 2 atom of the thiazole ring ionizes (loses H) to form a carbanion (negatively charged Carbon);
2. Carbanion then attacks the carbonyl group of pyruvate, alpha-KG, etc;
3. Attacking carbanion of the TPP at the carbonyl creates new attached compound
94
What is the Pentose Phosphate Pathway?
- ALTERNATIVE route for GLUCOSE;
- Occurs in the LIVER and CYTOSOL of cells;
- Does NOT generate ATP;
- Forms of NADPH for SYNTHESIS of fatty acids and steroids;
- Synthesis of RIBOSE for nucleotide and nucleic acid formation
95
What is similar between Glycolysis and the Pentose Phosphate Pathway?
- More complex than glycolysis and the reactions also occur in the CYTOSOL;
- As in glycolysis there is DEHYDROGENATION (remove an H and electrons), but NADP+ instead of NAD+ is the hydrogen and electron acceptor
96
What is the FIRST phase of the Pentose Phosphate Pathway?
1. OXIDATIVE nonreversible phase =
•One run of OXIDATIVE phase:
-3C6 + 6NADP+ → 3C5 + 3CO2 + 6NADPH + H+
-[Glucose 6-Phosphate → Ribulose 5-Phosphate]
97
What is the SECOND phase of the Pentose Phosphate Pathway?
2. a NONOXIDATIVE reversible phase =
One run of NONOXIDATIVE phase:
-3C5 → 2C6 + C3 (or ½ C6)
-[Ribulose 5-Phosphate → Glucose 6-Phosphate + Glyceraldehyde 3-Phosphate]
98
What is the overall process of the Pentose Phosphate Pathway?
Often shown as X2=
- 6C6 + 12NADP+ 4C6 + 2C3 + 6CO2 + 12NADPH + H+;
- Then: 2C3 → C6
* *For oxidation of one glucose resulting in 5C6
99
Where are the roles of Thiamin in the NONoxidative phase of the Pentose Phosphate Path?
Breakdown into scramble gives:
1. 2C5 → C7 + C3 – transketolase (thiamin = (moving a C2)
2. C7 + C3 → C4 + C6 – transaldolase = (moving a C3)
3. C4 + C5 → C6 + C3 – transketolase (thiamin) = (moving a C2 )
= 3C5 → 2C6 + C3
100
How does TPP (thiamin pyrophosphate) catalyze the Pentose Phosphate Path?
Tranksketolate = enzyme;
TPP = cofactor;
In the NONoxidative phase:
-TPP accepts a 2-carbon fragment from a 5-carbon ketose;
-Then transfers this fragment to a 5-carbon aldose to form a 7-carbon ketose
101
How does Thiamin affects nerve cells?
NOT a COENZYME here;
- Electrical activity of nerve cells is changed when antagonists (promoters) of thiamin are used;
- Thiamin itself may be involved in nerve impulse transmission by regulating sodium channels and in phosphorylation of proteins;
- TPP appears to be released when nerve impulses are stimulated
102
How Thiamin EXCRETED?
- EXCESS thiamin in various forms can be excreted INTACT or CATABOLIZED;
- Initially thiamin is BROKEN into pyrimidine and thiazole components
103
What happens to the pyrimidine and thiazole components from broken Thiamin?
- The two rings are further catabolized;
- Generates 20 or more metabolites;
- EX: 4-methyl thiazole 5-acetic acid and 2-methyl 4-amino 5-pyrimidine carboxylic acid
104
What is the RDA for Thiamin?
- Men = 1.2 mg/day adult
- Women = 1.1 mg/day
- Pregnancy = 1.4 mg/day;
- Lactation = 1.5 mg/day
105
How is Thiamin status tested?
- Add thiamin to HEMOLYZED whole blood or measure thiamin in blood or urine;
- Hemolyzed blood – erythrocytes (red blood cells) have been ruptured, releasing their contents;
- Erythrocyte Thiamin deficiency = >1.25;
- Urine thiamin deficiency = <27
106
What is Wernicke's Syndrome?
- Thiamin deficiency associated with ALCOHOLISM:
| - Neuropsychological complication;
107
What are the 3 problems alcoholics have with Thiamin?
1. Decreased food consumption = not enough dietary sources;
2. Liver damage decreases TDP formation = increased requirements of the vitamin, which then impairs TDP formation in the liver and ultimately impairs vitamin use
3. Decreased absorption = alcohol inhibits the expression of the carriers ThTr1 and ThTr2 and therefore inhibits Thiamin absorption
108
What other conditions have been linked to Thiamin deficiency?
- Congestive heart failure that may be due to diuretic use causing increased thiamin excretion and may be low intake;
- Other conditions that have resulted in thiamin deficiency are with TPN without thiamin included and excess glucose infusion
109
Is there a UL for Thiamin?
- No UL has been established
- 500 mg ingested daily for a month did not have any problems
- This level of supplementation helps those with maple syrup urine disease → also consume low protein helps with this disease
- Maple Syrup Urine disease – can’t fully metabolize BCAA’s
110
How can Thiamin supplementation be used a drug treatment?
-Helps patients with LACTIC ACIDOSIS by increasing pyruvate dehydrogenase activity and increases the conversion of pyruvate to acetyl-CoA;
-Thiamin is the coenzyme to this reaction → It decreases the conversion of pyruvate to lactic acid as more pyruvate is decarboxylated to acetyl-CoA to enter the TCA cycle;
AND
-Also a thiamin-responsive megaloblastic anemia that is treatable with high supplementation
111
How was Riboflavin (B2) discovered?
1917, originally called Vitamin G;
- Gyorgy showed that vitamin B2 cured egg white injury;
- Then in 1933, Gyorgy worked with Warner-Jauregg in Kuhn’s lab to feed thiamin-free extracts of yeast, liver, or rice bran and supplemented with thiamin – they prevented growth failure;
- 1934, Kuhn’s group identified the structure
112
What is the structure of Riboflavin?
-“Ribo” comes from ribose-like SIDE-CHAIN and “flavus” means yellow in Latin;
-Riboflavin main structure = Ribitol + Flavin
oFMN (coenzyme) = ADD a phosphate group
oFAD (coenzyme) = ADD a pyrophosphate + AMP
113
What is the main chemical characteristic of Riboflavin?
- Riboflavin and its conenzymes are particularly ALKALI (basic) and acid sensitive in the presence of LIGHT;
- DESTROYED BY LIGHT → When purified activity would be lost because of room light if acidic or alkaline conditions
114
What are the FOOD sources of Riboflavin?
- Animal foods are GOOD with MIlk being the MOST;
- Green veggies are GOOD;
- Fruit and cereals are MINOR
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What is the FORM of Riboflavin in foods?
- Milk, eggs, and enriched breads and cereals is either in FREE form or FMN or FAD or bound to protein;
- In most other foods, riboflavin is found as FMN and FAD
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What is the first step of Riboflavin digestion?
- HCl in stomach and enzymatic hydrolysis of the proteins frees the riboflavin from the protein attachments for activity of small intestine enzymes;
- FAD (FAD Pyrophosphate) → FMN (FMN Phosphatase) → Riboflavin
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What can happen when Riboflavin is digested with protein?
- Can result in histidine or cysteine BOUND to riboflavin as FAD or FMN;
- This form is either NOT ABSORBED or if absorbed is EXCRETED in the urine
118
What factors affect Riboflavin digestion/absorption?
- Animal sources better released in digestion and absorbed;
- Divalent metals (2 valence electrons) bind to riboflavin and FMN;
- Alcohol impairs absorption
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How is Riboflavin absorbed after digestion?
- FREE riboflavin is absorbed AFTER FAD and FMN are produced by actions of enzymes → HCl in the stomach
- Absorption is by a saturable, energy-dependent CARRIER mechanism in the proximal (beginning) small intestine;
- LARGE amounts can be absorbed by DIFFUSION (No carrier);
- ~95% of food riboflavin absorbed when intake is up to 25 mg
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What is the carrier for Riboflavin?
- Riboflavin transporter 2 (RFT2);
| - Carriers in proximal small intestine appear to be SODIUM INDEPENDENT, but do require energy!;
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What are the methods for absorption of Riboflavin into CELLS?
1. Diffusion or molecular penetration → Fat soluble
2. Diffusion of water via Osmosis to equalize solute concentrations
3. Facilitated diffusion through protein carrier → Fructose
4. Glucose and Amino acids → Cotransport
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What are the forms of PASSIVE absorption or diffusion (no energy)?
1. Simple - net movement from high to low conc.
2. Facilitated - high to low conc. through transport protein
3. Filtration - water and solute movement due to Hydrostatic Pressure
4. Osmosis - net movement of water through semi-permiable membrane from high to low water potential
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What happens to Riboflavin once absorbed into CELLS?
- ABSORBED riboflavin is converted back to FMN in the intestinal cells;
- Then again back to riboflavin for leaving the cell and entering the blood
- Riboflavin (GI) → FMN (cells) → Riboflavin (blood – carried by Albumin)
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How is Riboflavin transported in the BLOOD?
- Transported by several proteins, mostly ALBUMIN;
- Enters cells by riboflavin binding protein (some regulated by calcium/calmodulin)
- DIFFUSION occurs if blood levels are HIGH → Moves from high levels in the blood to lower levels within the cells WITHOUT energy
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How is Riboflavin converted to FMN
- in LIVER;
- Flavokinase converts riboflavin to FMN;
- Energy requiring ;
- Flavokinase is increased by ACTH, aldosterone, and thyroid hormones
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How is FMN converted to FAD?
FAD synthetase converts FMN to FAD ;
- Liver, kidney and heart have greatest amounts;
- FAD predominates in TISSUES, but have both FMN and FAD
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How do FMN and FAD become flavoproteins?
- FMN and FAD attach to APOPROTEINS to become flavoproteins that are enzymes involved in oxidation/reduction reactions;
- Apoproteins – the protein part of an enzyme WITHOUT its characteristic prosthetic group → FMN/FAD are the prosthetic groups
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What are the FUNCTIONS of Riboflavin?
- Plays a role in which hydrogen peroxide is produced from activated white blood cells;
- Major role in OXIDATION-REDUCTION reactions, especially Oxidative Decarboxylation
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What is Oxidative-Decarboxylation?
oxidation reactions in which a carboxylate group is removed, forming CO2
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What is the role of FAD (riboflavin) in the electron transport chain?
- Coenzyme to energy production and oxidative decarboxylation reactions!!;
- Accepts 2 hydrogens in the TCA cycle becoming FADH2;
- It then donates a pair of its electrons to carriers that enter the ETC to produce energy
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What is the role of FAD (riboflavin) in oxidative decarboxylation of Pyruvate?
- Pyruvate dehydrogenase complex reaction;
- FAD becomes reduces to FADH2 to accept electrons as pyruvate bind to acetyl-CoA;
- FADH2 is then oxidized by NAD+ and the electrons are transferred to the ETC
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Where is the role of Riboflavin in the TCA cycle?
- Oxidative decarboxylation of alpha-ketoglutarate.
- The decarboxylation and dehydrogenation of alpha- Ketoglutarate is mechanistically identical to to the pyruvate dehydrogenase reaction.
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What is the role of FAD if Fatty Acid Oxidation?
- Fatty acyl dehydrogenase reaction with "Fatty acid Oxidase";
- Performs the Acetyl-CoA dehydrogenase reaction and by conversion from FAD to FADH2 by dehydrogenation of Acetyl-CoA;
- This reduced FADH2 then goes to the ETC to use the electrons for energy
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What is the Sphingagine Oxidase rxn that requires FAD?
- Carries out SPHINOGSINE synthesis ;
| - Sphingosine = primary part of sphingolipids, a class of cell membrane lipids
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What is the Xanthine Oxidase rxn that requires FAD?
Involved in purine catabolism in liver;
- Hypoxanthine to xanthine to uric acid, delivers electrons and hydrogen directly to oxygen producing H2O2;
- contains iron and molybdenum
136
What is the Aldehyde Oxidase rxn that requires FAD?
EXs:
- Converts pyridoxal (vitamin B6) to pyridoxic acid for excretion;
- Retinal to retinoic acid (one of the active forms of vitamin A)
- Also forms H2O2
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What is the Pyridoxine Phosphate Oxidase rxn that requires FAD?
-FMN is used to convert PMP and PNP to PLP = the coenzyme form of vitamin B6
138
How is FAD needed in folate metabolism and utilization?
- Needed for synthesis of 5-methyl tetrahydrofolate (THF);
- High supplemental doses of FOLIC ACID can produce dihydrofolate (DHF);
- DHF is a derivative which is converted to tetrahydrofolic acid by dihydrofolate reductase
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How can someone overcome low functioning MTHFR of folate?
MASS ACTION can overcome MTHFR low function converting 5,10 methylene THF to 5-methyl THF or low vitamin B12 converting 5-methyl THF to THF
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What NEUROTRANSMITTERS require FAD?
-Dopamine and other amines, tyramine and histamine, require the enzyme MONOAMINE OXIDASE which requires FAD
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How does FAD regenerate Glutathione?
- Glutathione is an antioxidant that becomes OXIDIZED to prevent free radicals;
- Reduction of the oxidized form of glutathione (GSSG) to the reduced form (2GSH) is dependent on FAD-dependent glutathione reductase;
* One method to assess riboflavin status
142
How do Erol and sulfhydryl oxidases use FAD?
- FAD-dependent;
| - Form DISULFIDE BONDS (oxidation) and leads to protein folding of SECRETORY proteins
143
How do Thiredoxin reductase and glutaredoxin reductases use FAD?
- Transfer reducing equivalents from NADPH + H+ through FAD to reduce DISULFIDE BONDS (oxidation) within oxidized form of thioredoxin or glutaredoxin;
- Thioredoxin or glutaredoxin then provide electrons and hydrogens (reduces) to ribonucleotide reductase for conversion of ribonucleotides to deoxyribonucleotides
144
How does L-amino Oxidase use FMN?
-Dehydrogenation of L-amino acids to imino acids
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What is an IMINO Acid?
- Any molecule that contains BOTH imino (>C=NH) and carboxyl (-C(=O)-OH) functional groups;
- Amino acids containing a SECONDARY amine group are sometimes named imino acids (the only proteinogenic amino acid of this type is PROLINE)
146
What is the difference between Imino Acids and IMIDIC acids?
Imidic Acids contain the group -C(=NH)-OH;
| -NOT the same
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How is Riboflavin excreted?
- Riboflavin is excreted in the urine INTACT;
| - When take a vitamin pill with riboflavin get bright yellow or orangish yellow urine
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What is the RDA for Riboflavin?
- Men = 1.3 mg/day
- Women = 1.1 mg/day;
- Amounts greater than 120 mcg/day or 80 mcg/g creatinine in urine is considered a marker of ADEQUATE INTAKE;
- NO UL
- 400mg used to tread migraines
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How is nutritional adequacy of Riboflavin tested?
- Activity of red blood cell glutathione reductase WITH and WITHOUT added FAD is used for testing adequacy
- 1.4 is DEFICIENT
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What is the deficiency of Riboflavin?
ARIBOFLAVINOSIS;
- Not a technical deficiency disease;
- Results in problems with tongue, lips, mouth, dermatitis, anemia, and peripheral nerve dysfunction
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What occurs in people with C677>T MTHFR and low riboflavin?
-Increase HOMOCYSTEINE;
-Homocysteine – Non-protein alpha-amino acid; homologue of Cysteine containing an extra methyl bridge=
•Synthesized from methionine → Can be reused back to methionine or turned into cysteine with the help of B vitamins
•*High levels are linked to CVD → increases risk of endothelial injury which leads to vascular inflammation;
-Conversion of tryptophan to niacin is reduced or eliminated
-Coenzyme form of vitamin B6 is lower
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What is the AI and UL for Choline?
- Historically NONESSENTIAL;
- Men = 550 mg/day;
- Women = 425 mg/day;
- UL is 3.5 g/day – hypotension, sweating, diarrhea, and a fishy odor;
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Choline is a PRECURSOR for....
- Acetylcholine
- Phosphatidylcholine
- Methyl donor betaine;
* *Found in the diet FREE or as apart of compounds
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What makes Choline possible NONESSENTIAL?
- Choline is synthesized de novo by synthesis from phosphatidyl ehtanolamine and this is dependent on methionine, folate, and vitamin B12;
- [De novo = synthesis of complex molecules from simple molecules such as sugars or amino acids]:
- Healthy men with normal status for folate and vitamin B12 fed a choline-deficient diet develop liver damage
155
How is Choline Catabolism?
-Functions with choline dehydrogenase (1), dimethylglycine dehydrogenase (4), and sarcosine (monomethylglycine) dehydrogenase (5) require FAD
156
What are the choline related compounds or metabolites?
- Betaine aldehyde;
- Betaine;
- Dimethylglycine;
- Sarsosine;
- Glycine;
- Phosphocholine;
- Phosphatidylcholine;
- Sphingopmyelin;
- Choline phospholipids
157
How is Choline utilized in the body?
- PANCREATIC enzymes FREE choline;
- Choline is ABSORBED in the small intestine via transporter proteins;
- Choline is absorbed into PORTAL blood, but any phosphatidylcholine enters the LYMPH in chylomicrons;
- Phosphatidylcholine – phospholipids with choline incorporated as a headgroup → Lipid so MUST travel through the lymph;
- TISSUES take up choline by a carrier mechanism and by diffusion
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What is Niacin (B3)?
-NIACIN is a generic descriptor for nicotinic acid (pyridine-3-carboxylic acid) and nicotinamide (nicotinic acid amide)
159
When was Niacin discovered?
- Nicotinic acid was isolated as a pure chemical in 1867;
| - 1937 that it was demonstrated as the anti-black-tongue factor in dogs and the anti-pellagra vitamin for humans
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What was the original belief regarding Pellagra?
- Thought pellagra was due to a deficiency of TRYPTOPHAN in corn even though the pathway of tryptophan to niacin had not been discovered at that time;
- Pathway not discovered until after both forms of niacin shown to be antipellagragenic;
- Also thought to be an Infectious disease
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What made Pellagra very common in the SE United States?
- Corn was not treated with alkali as in Mexico and the niacin was NOT AVAILABLE from the corn;
- The diet had pork fat and not high quality protein for the most part so tryptophan to niacin would be limited;
- Early 1900s psychiatric hospitals in the Southeast were filled with patients suffering from DEMENTIA from pellagra
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Who proved pellagra was NOT an infectious disease?
- Joseph Goldberger and co-workers contaminated themselves with materials from pellagra patients;
- He was shown to be correct, he died in 1929 when pellagra epidemic was at its height
- Epidemic ended with federal program of ENRICHMENT of grains and improved economy after World War II
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What are the 4 D's of Pellagra?
- Dermatitis;
- Dementia;
- Diarrhea;
- Death
164
What are the food sources of Niacin?
- Fish and other animal flesh products are GOOD sources;
- Enriched and whole grains also GOOD sources;
- Coffee and tea contain, green vegetables and milk have LOWER amounts
165
What are the forms of Niacin in animals products?
In animals found in coenzyme forms NAD and NADP, but with slaughter, degraded to nicotinamide
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How is Niacin found COVALENTLY bound in foods?
- Niacytin is when bound to complex CARBS and ;
- Niacinogens when bound to small PEPTIDES → these are found primarily in corn, but also in wheat and some other cereal grains;
- Chemical treatment with ACIDS, such as lime water, FREES the niacin, otherwise only about 10% is available from corn due to stomach acid releasing some;
- Niacin is NOT readily bioavailable from corn!
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What are the COENZYME forms of Niacin?
-NAD (catabolic) and NADP (anabolic)
-Oxidized forms = NAD or NAD+; NADP or NADP+
[Oxidized = LOSE electrons and become more positive!!]
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What amino acids can be used to synthesize niacin in the form of NAD?
- In the LIVER, NAD can be synthesized from tryptophan, but only about 3% of metabolized tryptophan (amino acid) converted to NAD;
- Tryptophan → NAD = makes Niacin a NONESSENTIAL Vitamin;
- Estimated need 60 mg tryptophan to produce 1 mg NAD
169
What happens to the NAD and NADP created from Tryptophan?
-NAD and NADP converted to nicotinamide by enzymes Glycohydrolase and Pyrophosphate
170
How must NAD/NADP be digested?
- Must be digested to NICOTINAMIDE for ABSORPTION;
| - Pyrophosphatase REMOVES phosphate off NADP and glycohydrolase FREES nicotinamide
171
How is Niacin absorbed in the small intestine?
- Niacin in NORMAL concentrations in diet is absorbed by a sodium-dependent carrier by FACILITATED diffusion;
- LARGE doses absorbed by PASSIVE diffusion
172
How is Niacin found in the PLASMA?
- Found primarily as NICOTINAMIDE, but some nicotinic acid can be found in plasma;
- Some of NICOTINIC ACID is bound to PROTEINS
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How does Niacin enter CELLS?
- Nicotinamide eneter by SIMPLE DIFFUSION;
| - Carriers required in the KIDNEY TUBULES and RED BLOOD CELLS
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What happens to the Nicotinamide once it enters CELLS?
- Converted to coenzyme forms NAD and NADP and these forms TRAP the vitamin within cells;
- COENZYMES are the form found WITHIN the CELLS;
- LIVER can convert NICOTINIC ACID to coenzymes
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What is the main function of NAD/NADP?
~200 enzymes, primarily DEHYDROGENASES that require the coenzymes NAD or NADP;
EX: glycolysis, oxidative decarboxylation of pyruvate to acetyl-CoA, oxidation of acetyl-CoA in the TCA cycle, beta-oxidation of fatty acids, and oxidation of ethanol
176
How is NAD used in the catabolism of B6?
- NAD required by ALDEHYDE DEHYDROGENASE for catabolism of vitamin B6 in form of pyridoxal to pyridoxic acid for EXCRETION
- Niacin is needed to BREAKDOWN Vitamin B6 for utilization and then excretion
177
What is the role of NAD as a coenzyme?
- Transfer electrons and hydrogens from metabolic intermediates to the electron transport chain;
- One H of the substrate goes to NAD to create NADH + H+;
- CANNOT generate energy through the ETC without Niacin
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What is the ETC couple with to generate ATP?
- Oxidative phosphorylation and production of ATP;
| - Oxidative Phosphorylation – mitochondria released the energy found in oxidated nutrients to create ATP
179
What is the function of NADPH?
- REDUCING AGENT in many biosynthetic pathways such as fatty acids, cholesterol and steroid hormones → ANABOLIC coenzyme!;
- Also proline synthesis, deoxyribonucleotide synthesis, and glutathione, vitamin C, and thioredoxin regeneration;
- FOLATE metabolsim requires NADPH;
* Addition of the –PO4 group allows for the reaction to run in reverse rxn and not be dependent on NAD concentrations
180
What is the NONRedox role of Niacin?
-Post-translational modification of proteins associated with chromosomes and formation of cyclic ADP-ribose
181
How do NAD and the cyclic ADP-RIbose function in the NEURONS?
-NAD glycohydrolases and the cyclic ADP-ribose functions as SECOND MESSENGER to control ryanodine receptors and release calcium from intracellular stores especially in neurons
182
How do NAD and the cyclic ADP-RIbose function in IMMUNE RESPONSE?
-Transfer of mono ADP-ribose to proteins on cell surfaces for IMMUNE RESPONSE;
-ADP-ribose transfer is performed by mono ADP-ribosyl transferases (ARTs);
-There are also poly ADP-ribose polymerases (PARP) that also use NAD;
ADP-ribose transfer plays a role in DNA repair, replication and transcription, and chromatin structure
183
How is Niacin RECYCLED?
- NAD and NADP are DEGRADED by glycohydrolases and pyrophosphatases to nicatinamide and ADP-ribose;
- Then can be recycled or converted to excretion products
184
What is the breakdown of Niacin?
Breakdown = NAD/NADP → [glycohydrolases and pyrophosphates] → nicatinamide
185
How is Niacin reabsorbed?
- Nicotinamide and nicotinic acid are actively REABSORBDED from glomerular filtrate;
- Glomerular filtrate – the filtrate that passes from the lumen of the glomerular capillary to the space of Bowman's capsule at the top of the kidney
186
How is Nicotinamide EXCRETED?
-Methylated nicotinamide is converted in the LIVER to a variety of excretion products
-Metabolites include =
•N’methyl nicotinamide (NMN) at 20 to 30%
•N’methyl 2-pyridone 5-carboxamide (2-pyridone) at 40 to 60%;
•N’methyl 4-pyridone carboxamide (4-pyridone)
187
How is Nicotinic Acid EXCRETED?
Nicotinic acid is mainly converted to N’methyl nicotinic acid
188
In what form is Niacin NOT excreted?
Very little of the vitamin forms themselves without catabolism are excreted → Not excreted whole
189
What are Niacin Equivalents (NE)?
- Recommendation for Niacin;
| - Account for the 1 mg of niacin that can be produced from~60 mg of tryptophan
190
What is the RDA for Niacin?
- Based on the excretion of niacin metabolites in the urine: ≥1 mg/day of NMN;
- Men = 16 mg/day
- Women = 14 mg/day ;
* DIET usually contains 900 mg of tryptophan or 15 NEs
191
What is the UL for Niacin?
- Based on flushing (vasodilatory) effects by nicotinic acid;
- 35 mg/day from supplements and fortified foods;
- Nicotinamide does not cause flushing but it is believed that it is covered with flushing effects by nicotinic acid;
- Newer extended release medicines are helpful in REDUCING risks of toxicity
192
How can Nicotinic Acid be used to treat hypercholesteremia (DRUG)?
-Large doses up to 6 g/day;
-Lowers total cholesterol, triglycerides, LDL; increases HDL;
Mechanism includes:
-Inhibition of lipolysis in adipose tissue
-Reduction of VLDL secretion by liver and this reduces LDL
-Inhibition of diacylglycerol acyltransferase in the liver for inhibition of triglyceride synthesis
193
What are other actions of Nicotinic Acid?
- Nicotinic acid binds to some G-protein-coupled receptors for inhibition signals;
- Also binds to peroxisome proliferator-activated receptor gamma (PPARgamma) in macrophages and induces prostaglandin synthesis
194
What are Prostaglandins?
-Group of lipid compounds that are derived enzymatically from fatty acids → mediators and have a variety of strong physiological effects, such as regulating the contraction and relaxation of smooth muscle tissue
195
How is Niacin status assessed?
- LOW excretion and DEFICIENCY =
| - Urinary excretion of <0.5 mg N’ methyl nicotinamide/1 g of creatinine
