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MARGINAL COMPOUDS

semi vitamins
Presented by

NAGI Moh ELFATIH

number of organic compounds have clear metabolic functions; they can be synthesized in the body ,but it is possible that under some circumstances endogenous synthesis may not be adequate to meet requirements Some were considered as vitamines once but the most suitable term for them all is quasi vitamins

The list of quasi-vitamins includes Factors required for some species other than man and required in man in certain conditions Choline Carnitine Myo-inositol Factors with certain metabolic functions but less evidence for essentiality Co Q10 Lipoic acid bioptreins and others

CARNITINE
-hydroxy--N,N,N trimethylaminobutyrate quaternary ammonium compound two stereoisomers L carnitine and D carnitine

Biologically active forms L-carnitine

sources
Diet Biosynthesis Supplements

biosynthesis
From two essential amino acids
lysine and methionine

primarily in the liver and kidneys Requirements for synthesis


Iron Vitamins C and B6

Dietary Sources
Breast milk --- contains 2895 nmol of carnitine per milliliter Red meat Milk and Dairy products Fish

materials of plant origin tend to be low in carnitine, whereas those derived from animals tend to be rich in the factor

supplements
L-carnitine most widely available and least expensive Acetyl L-carnitine Propionyl L-carnitine

metabolism
Absorption active transport dependent on Na+ cotransport Passive diffusion High efficiency Rapid uptake

Transport released slowly from tissues High soluble in plasma in both the free and acetylated forms 3089 M taken up, against concentration gradients, by peripheral tissues by high-affinity, Na+dependent transporters located principally in the skeletal muscle, which contains some 95% of the bodys carnitine

The L-carnitine level in healthy adults


umol/L Plasma free L-carnitine level Plasma acetyl-L-carnitine 40~50 3~6

Plasma acyl-L-carnitine except acetylL-carnitine


Plasma total L-carnitine level

<5
50~60

Lower 10~20% in women

carnitine concentrations of skeletal muscles are typically 70-fold that of plasma turnover of carnitine in muscle is relatively slow( ~8 days) but increased substantially by exercise

Excretion carnitine is highly conserved by the human kidney, which reabsorbs more than 90% of filtered carnitine Renal excretion of carnitine adapts to the level of carnitine intake free form or as short-chain acylcarnitine esters

Some conditions increase excretion of carnitine Propionic aciduria Methylmalonic aciduria Supplemental dietary choline

Metabolic Function
transport of fatty acids (fatty acyl-CoA) from the cytosol into the mitochondrial matrix for oxidation as sources of energy The fatty acids with chain lengths of 12 or fewer carbons enter mitochondria without the help of membrane transporters. Those with 14 or more carbons, the majority of the FFA obtained in the diet or released from adipose tissue, cannot pass directly through the mitochondrial membranesthey must first undergo the three enzymatic reactions of the carnitine shuttle

The carnitine acyltransferases are actually a family of related enzymes. Six carnitine acyltransferases with different but overlapping chain-length specificities have been isolated from mitochondria At least five carnitine transporters have been cloned

Hormone function
Carnitine have biological actions similar to those of glucocorticoids bind the glucocorticoid receptor and effect the receptor-mediated release of cytokines

Physiological effects
Atherosclerosis There may be a link between dietary consumption of carnitine and atherosclerosis Antioxidant effects protective effect against lipid peroxidation of phospholipid membranes and against oxidative stress induced at the myocardial and endothelial cell level.

Health effects
Hepatic function
protect against ammonia-induced encephalopathy in cirrhotics

Renal function
studies have suggested that carnitine administration to dialysis patients can increase hematocrit, allow a lower erythropoietin dose, and reduce intradialytic hypotension and fatigue

Diabetes
A clinical trial found carnitine to reduce fasting plasma glucose levels and to increase fasting triglycerides in type II diabetics

Cardiovascular function
benefit cardiac function produce effects on prostaglandins that are associated with cardioprotection reduce myocardial injury after ischemia and reperfusion

Neurologic function
studies have shown that acetylcarnitine treatment can induce the release of acetylcholine in the striatum and hippocampus, Alzheimers disease patients carnitine attenuate progression of several parameters of behavior, disability, and cognitive performance reduce attention problems and aggressive behavior in boys with attention-deficit hyperactivity disorder

Male reproductive function


Epididymal tissue and spermatozoa typically contain high concentrations of carnitine Studies indicate that carnitine levels are related to sperm count, motility, and maturation carnitine supplementation can improve sperm quality

Thyroid function Carnitine appears to be a peripheral agonist of thyroid


hormone action

Carnitine deficiency
metabolic disorder in which body levels of carnitine, is less than what is needed for the normal function of the body. True carnitine deficiency is not known to occur in healthy people Primary Secondary

primary carnitine deficiency is a rare genetic disorder caused by a mutation in the protein that transports carnitine presents in childhood and can be fatal without treatment. Other names for these conditions include carnitine palmitoyltranserase I or II deficiency and carnitine-acylcarnitine translocase deficiency.

Secondary carnitine deficiency, more common than primary deficiency, people at risk strict vegetarians protein-energy malnutrition administration of the anticonvulsant valproic acid and other drugs metabolic organic acidemias acidurea premature infants patients undergoing hemodialysis

Signs and Symptoms of Deficiency Some people with primary carnitine deficiency are asymptomatic Symptomatic disease appears as
liver dysfunction Cardiomyopathy and cardiomegaly Muscle fatigue and weakness abdominal cramps Hypoketotic hypoglycemia Diarrhea Anemia

Diganosis of carnitine deficiency


Measurement of plasma carnitine levels of individuals with carnitine deficiency will show extremely reduced plasma free carnitine levels (<5 M, normal 25-50 M). Urine carnitine excretion in individuals with carnitine deficiency who are on carnitine supplementation is typically very high

Treatment of carnitine deficiency high dose carnitine supplementation, which must be continued for life. Individuals who are identified and treated at birth have very good outcomes, including the prevention of cardiomyopathy

CHOLINE
2-hydroxy-N,N,N-trimethylethanaminium quaternary ammonium compound freely soluble in water and ethanol, but insoluble in organic solvents. strong base methyl donor ==prominent feature of its chemical structure due to its triplet of methyl groups

Dietry forms
widely distributed in foods mostly in the form of phosphatidylcholine (lecithin), Some dietary choline is present as the free base or sphingomyelin

sources in diets
egg yolk glandular meats (e.g., liver, kidney, brain) soybean products, wheat germ peanuts

supplements
Available as choline salts Added to infant formula also

metabolism
Digestion
Choline is released from phosphatidylcholine by hydrolysis in the intestinal lumen, an action of phospholipases 3 type of phospholipases act on phosphatidylcholine

Phospholipase A2 Phospholipase A1 Phospholipase B

Cleavage sites of phospholipases


Phospholipase A1 Phospholipase B

Phospholipase A2
H2C O

O C R

O R C O

CH O

H2C

Phospholipase C

Phospholipase D

most of the phosphatidylcholine that is ingested is absorbed as lysolecithin lysolecithin is reacylated to phosphatidylcholine in the intestinal mucosal cells 30% of dietary phosphatidylcholine is absorbed intact into the lymphatic system bound to chylomicron the resr is converted to glycerylphosphorylcholine in the intestinal mucosa and to free choline in the liver

When free choline is consumed a large amount (e.g., nearly two-thirds) is catabolized by intestinal microorganisms to the end product trimethylamine
The remaining portion is absorbed intact

Choline is absorbed in the upper portion of the small intestine by a saturable, carrier-mediated process

Hgffd

Tissue distribution
present in all tissues as an essential component of phospholipids in membranes of all types. stored in the greatest concentrations in brain, liver, kidney in forms of phosphatidylcholine and sphingomyelins Placenta accumulate large amounts of acetylcholine

Biosynthesis
three ways of phosphatidylcholine biosynthesis: Methylation of ethanolamine, Reaction of cytidine diphosphate Phospholipid base exchange

Choline is released in free form in the tissues by the actions of phospholipase C peripheral tissues also contain phospholipase B activity and can therefore produce glycerylphosphorylcholine The brain also contains phospholipase D, which cleaves free choline directly

Metabolic Functions
As phosphatidylcholine A structural element of biological membranes A promoter of lipid transport (as a lipotrope) Surfactant

As acetylcholine, it is a neurotransmitter, occurring primarily in the parasympathetic nervous system ,autanomic ganglia, neuromusclar junction and CNS

As a component of platelet-activating factor it is important in clotting, inflammation, uterine ovum implantation, fetal maturation, and induction of labor As a component of plasmalogen, it has a role in myocardial function

As a source of labile methyl groups, after its irreversible oxidation to betaine, it is a source of labile methyl groups for transmethylation reactions in the formation of methionine from homocysteine, This function links choline to folate metabolism choline constitutes an important dietary source of labile methyl groups for homocysteine transmethylation

Health Effects
choline loading may be beneficial to patients with diseases involving deficiencies of cholinergic neurotransmission 1. enhance cognitive performance, 2. increase electrophysiological responsiveness; 3. provide some protection against alcohol and other neurotoxic agents 4. help in the treatment of tardive dyskinesia 5. success to improve free memory in subjects without dementia 6. diminish short-term memory losses associated with Alzheimers disease

deficiency
Risk of deficiency Poor nutrition, imbalance in the diet liver disease methionine,folic acid and vitamin B-3 deficiency Methotrexate

Mild choline deficiency can cause


fatigue, insomnia, frequent memory loss, and nerve-muscle imbalances.

Extreme choline deficiency can cause


liver dysfunction, cardiovascular disease, impaired growth, abnormalities in bone formation, lack of red blood cell formation, infertility, respiratory distress and failure to thrive in newborns, kidney failure, anemia, and high blood pressure.

Toxicity
very low Appears as symptoms of Growth depression, impaired utilization of vitamin B6 dizziness, nausea, and diarrhea

Myo inositol
Inositol is a carbohydrate It is sugar alcohol water-soluble hydroxylated, cyclic six-carbon compound nine possible stereoisomeric forms Myo inositol is the only biologically active form

Dietary Sources
occurs in foods and feedstuffs in three forms: free myo-inositol, phytic acid and Inositol containing phospholipids

The richest sources of myo-inositol are the seeds of plants Predominant form occurring in plant materials is phytic acid Because most mammals have little or no intestinal phytase activity, phytic acid is poorly utilized as a source of either myo-inositol or phosphorus

In animal products, myo-inositol occurs in free form as well as in inositol-containing phospholipids


The richest animal sources of inositol are organ

meats

Human milk is relatively rich in myo-inositol (colostrum, 200500 mg/liter; mature milk, 100200 mg/liter) It is added to many prepared infant formulas

Biosynthesis
from Glucose 6 phosphate in the kidneys 4 g/day

supplements

Absorption
active transport uptake of myo-inositol from the small intestine is complete absorption of phytic acid, however, depends on the ability to digest that form and on the amounts of divalent cations in the diet/meal Dietary cations (particularly Ca2+) can reduce the utilization of phytate by forming insoluble (and, thus, nondigestible and nonabsorbable) phytate chelates

Absorption of phospholipid myo-inositol; is probable that it is analogous to that of phosphatidylcholine

Transport
Transported in the blood predominantly in the free form; A small but significant amount of phosphatidylinositol (PI) is found in association with the circulating lipoproteins

Tissue uptake
Free myo-inositol appears to be taken up by active transport process in some tissues (kidney, brain) by carrier-mediated diffusion in others (liver). The active process requires Na+ and energy, and is inhibited by high levels of glucose.

Metabolism
Free myo-inositol is converted to PI within cells either by de novo synthesis by reacting with the liponucleotide cytidine diphosphate (CDP)-diacylglycerol,or by an exchange with endogenous PI Phosphatidylinositol sequentially phosphorylated to the monophosphate (phosphatidylinositol 4-phosphate, PIP) and diphosphate (phosphatidylinositol 4,5-diphosphate, PIP2) forms by membrane kinases

myo-inositol-containing phospholipids enriched in stearic acid at sn1-position and arachidonic acid at sn2-position

turnover of the myo-inositol phospholipids


cellular phosphomonoesterases catabolize PIPs to yield PI. PI synthetase functions (in the reverse direction) to break down that form to yield CDP-diacylglycerol and myo-inositol The kidney perform most of the catabolism of myoinositol, first clearing it from the plasma and converting it to glucose and, then, oxidizing it to CO2 via the pentose phosphate pathway

Metabolic Functions
active form is phosphatidylinositol, effecter of the structure and function of membranes enzyme modulater source of arachidonic acid for eicosanoid production mediator of cellular responses to external stimuli

effecter of the structure and function of membranes


activator of a microsomal Na+,K+ ATPase effective anchor for the hydrophobic attachment of proteins to membranes Regulation of Vesicle Transport Rearrangement of actin cytoskeleton Recruitment of Tyrosine kinases

mediator of cellular responses to external stimuli

enzyme modulater
constituent of acetyl-CoA carboxylase stimulator of tyrosine hydroxylase Factor bound to alkaline phosphatase and 5-nucleotidase membrane anchor for acetylcholinesterase

Lipoic Acid
organosulfur compound derived from octanoic acid. contains two sulfur atoms (at C6 and C8) connected by a disulfide bond

Dietary Sources
present in a wide variety of foods but generally at low levels.
The best sources are tissues rich in mitochrondia (e.g., heart, kidney) tissues rich in chloroplasts (i.e., dark green leafy vegetables)

Metabolic Functions
Coenzyme essential cofactor for the oxidative decarboxylations of keto acids where, linked to the -amino group of a lysine residue of the enzyme dihydrolipoyl transacetylase, it is one of several prosthetic groups in multienzyme complex. In that catalysis, the amide form, lipoamide, undergoes reversible acylation/deacylation to transfer acyl groups to CoA as well as reversible redox ring opening/closing, which is coupled with the oxidation of the -keto acid

Antioxidant
The ability to undergo interconversion between disulfide (lipoic acid) and sulfhydryl (dihydrolipoic acid) forms enables this metabolite to function as a metabolic antioxidant, quenching reactive oxygen species and other free radicals and chelating prooxidant metal ions. Its function in this regard is related to those of other metabolic antioxidants in the network of protection against oxidative stress.

Health Effects
it has been proposed that lipoic acid may have value in the prevention and/or treatment of other chronic dis-eases associated with oxidative stress Recent interest has centered on the prospective benefits of lipoic acid in diabetes and neurodegenerative diseases

Coenzyme Q10
Ubiquinone tetra-substituted 1,4-benzoquinone derivativeswith isoprenoid side chains of variable length essential component of the mitochondrial electron transport chains of most prokaryotic and all eukaryotic cells

sources
Rich sources of dietary coenzyme Q10 include mainly meat, poultry, and fish. Other relatively rich sources include soybean and canola oils, and nuts. Fruits, vegetables, eggs, and dairy products Supplements

Biosynthesis Coenzyme Q10 is synthesized in most tissues. Requierment mevalonate, tyrosine, molecular oxygen, S-adenosylmethionine. endogenous tissue biosynthesis is sufficient to support membrane saturation levels

Metabolism
Absorption ubiquinones are absorbed, transported and taken up into cells by mechanisms analogous to those of the tocopherols Tissue distribution In all membranes in the cell. Relatively great concentrations of CoQ10are found in the liver, heart, spleen, kidney, pancreas, and adrenals.

Tissue ubiquinone levels increase under the influence of oxidative stress, cold acclimation, and thyroid hormone treatment, and decrease with cardiomyopathy, other muscle diseases, and aging

Metabolic Function
Mitochondrial respiratory chain component electron acceptors for complexes I and II of mitochondrial electron transport chains. They pass electrons from flavoproteins (e.g., NADH or succinic dehydrogenases) to the cytochromes via cytochrome b5 They perform this function by undergoing reversible reduction/ oxidation to cycle between the 1,4quinone (oxidized) and 1,4-dihydroxybenzene (reduced) species

Antioxidant membrane-bound antioxidant protects and thus spares -tocopherol in subcellular membranes. Along with -tocopherol, -carotene, and selenium, CoQ10 has been shown to provide significant protection from lipid peroxidation in animals. In some tissues (e.g., liver) its effect appears to be greater than those of the other antioxidant nutrients.

Health effects
Clinical trials with humans have indicated benefits of supplemental CoQ10 of several types Modest improvements in symptoms with Parkinsons disease patients. reduce headache frequency reduce dyspnea, edema, and the frequency of hospitalization in Congestive heart failure decrease systolic and diastolic blood pressure in hypertensive patient reduce subsequent myocardial events and cardiac deaths after myocardial infarction improve endothelial function of peripheral arteries of dyslipidemic patients with type II diabetes.

Tetrahydrobiopterin
Tetrahydrobiopterin can be synthesized from GTP It is the coenzyme for mixed function oxidases: phenylalaninehydroxylases , tyrosine hydroxylases, tryptophan hydroxylases; alkyl glycerol monoxygenase, nitric oxide synthase . In addition to its coenzyme role, tetrahydrobiopterin has a direct effect on neurons, acting to stimulate dopamine release via a cAMP-dependent protein kinase and a calcium channel

A deficit in tetrahydrobiopterin biosynthesis and/or regeneration can result in phenylketonuria (PKU) from excess phenylalanine concentrations or hyperphenylalaninemia (HPA). The chronic presence of PKU can result in severe brain damage, including symptoms of mental retardation, microcephaly, speech impediments such as stuttering, slurring, and lisps, seizures or convulsions, and behavioral abnormalities, among other effects

Glutathione
Glutathione (gamma-glutamyl-cysteinylglycine ) Tripeptide It is an antioxidant, preventing damage to important cellular components caused by reactive oxygen species such as free radicals and peroxides

gamma peptide linkage between the amine group of cysteine (which is attached by normal peptide linkage to a glycine) and the carboxyl group of the glutamate side-chain

Biosynthesis

not an essential nutrient (meaning it does not have to be obtained via food), since it can be synthesized in the body from the amino acids L-cysteine, L-glutamic acid, and glycine. all cells in the human body are capable of synthesizing glutathione, liver is the main organ of glutathione synthesis

Glutathione exists in both reduced (GSH) and oxidized (GSSG) states

Food sources
Foods containing glutathione and glutathionestimulating chemicals Tomatoes, garlic, onions and green peppers

Function
Glutathione has multiple functions: It is the major endogenous antioxidant produced by the cells, participating directly in the neutralization of free radicals and reactive oxygen compounds, as well as maintaining exogenous antioxidants such as vitamins C and E in their reduced (active) forms

GSH is known as a substrate in both conjugation reactions and reduction reactions, catalyzed by glutathione S-transferase enzymes in cytosol, microsomes, and mitochondria. However, it is also capable of participating in non-enzymatic conjugation with some chemicals.

It is used in metabolic and biochemical reactions such as DNA synthesis and repair, protein synthesis, prostaglandin synthesis, amino acid transport, and enzyme activation.

Regulation of the nitric oxide cycle, which is critical for life but can be problematic if unregulated It has a vital function in iron metabolism.

Glutathione as antioxidant

HHHH

phytochemicals

Functions

Hormonal action - Isoflavones, found in soy, imitate human estrogens and help to reduce menopausal symptoms and osteoporosis.
Stimulation of enzymes - Indoles, which are found in cabbages, stimulate enzymes that make the estrogen less effective and could reduce the risk for breast cancer. Other phytochemicals, which interfere with enzymes, are protease inhibitors (soy and beans), terpenes (citrus fruits and cherries). Interference with DNA replication - Saponins found in beans interfere with the replication of cell DNA, thereby preventing the multiplication of cancer cells. Capsaicin, found in hot peppers, protects DNA from carcinogens. Anti-bacterial effect - The phytochemical allicin from garlic has antibacterial properties. Physical action - Some phytochemicals bind physically to cell walls thereby preventing the adhesion of pathogens to human cell walls.

There are currently many phytochemicals in clinical trials for a variety of diseases. Lycopene from tomatoes, for example, has been tested in human studies for cardiovascular diseases and prostate cancer. These studies, however, did not attain sufficient scientific agreement to conclude an effect on any disease. Lutein and zeaxanthin are suspected to inhibit macular degenerationand cataracts, there was insufficient scientific evidence from clinical trials for such specific effects or health claims.