Water soluble vitamins Dr.S.Chakravarty, MD. A- ATP B- BIOTIN C- CO 2 REM - VOMIT MAIN ATP SYNTHESIS DECREASEDATP Na+K+ PUMP FAILURE CELLS SWELL.

Water soluble vitamins

Dr.S.Chakravarty, MD

A- ATPB- BIOTIN C- CO2 REM - VOMIT

MAIN ATP SYNTHESIS

DECREASEDATP Na+K+ PUMP FAILURE CELLS SWELL AND DIE

KAPLAN Step 1 notes

V.Imp SOURCE OF e0

-1 for ETC

Left untreated death !!

U T

DNA and RNA synthesis

KAPLAN Step 1 notes

SUBACUTRE COMBINED DEGENERATION

1)Regeneration of TETRAHYDROFOLATE (ACTIVE FOLATE )DNA and RNA synthesis

ANYTHING THAT DAMAGES LIVER OR ANYTHING THAT INCTREASED AST/ALT ACTIVITY INCREASED NEED FOR PLP

LESS HEMESMALL RBCs IRON NOT USED IRON DEPOSITED IN PRECURSORS OF RBCSSIDEROBLASTS

KAPLAN Step 1 notes

ATP

STOMACH ACIDITY AND VIT C Fe+3 Fe +2

CoA

KAPLAN Step 1 notes

Thiamine : B1 • Source : unpolished rice and whole wheat.(Aleurone layer OF CEREALS )• PARBOILED RICE IS RICH IN THIAMINE

Thiamin status is affected by:1. Food processing – washing, polishing etc.

2. Anti-thiamine factors – Fresh water and shell fish (thiaminases), pyrithiamine.

3. Ethanol ingestion / c/c alcoholism (MCC cause of DEFICIENCY ) Reduces thiamin intake Impairs intestinal absorption Alters phosphorylation of thiamin Increases excretion

Functions of B1:1. Enzyme cofactor: (Thiamine pyrophosphate TPP

or TDP)

A. Oxidative decarboxylation reactions Pyruvate dehydrogenase α-ketoglutarate dehydrogenase α-keto acid dehydrogenase – branched chain

amino acid metabolim.

B. Transketolation reactions Transketolase – HMP pathway

2. Thiamine Triphosphate (TTP)• Nerve conduction

1. Phosphorylation of membrane ion channels

2. Regulates sodium conductance

• Neurotransmission

1. Acetyl choline, Glutamate and GABA synthesis and utilization

2. Increase neurotransmitter levels in brain.

Measurement of thiamine status:

• Erythrocyte transketolase activity: Lab investigation for B1 deficiency.

xylulose-5-p + Ribose-5-p (ketose) (aldose)

Glyceraldehyde-3-p + Sedo-heptulose-7-p (aldose) (ketose)

Deficiency of B1:

• Beriberi Wet beriberi Dry beriberi Infantile beriberi

• Wernicke-Korsakoff syndrome:

• Polyneuritis:

Wet Beri Beri:Cardiovascular manifestations edema palpitations breathlessness fatigue distended neck veins

cause of death: high ouput cardiac failure

Shoshin beriberi: cyanosis, shock, cardiomegaly

Biochemical basis of wet beriberi:

Pyruvate Acetyl CoA (-) Lactate

Acidosis

Depression of vasomotor center

Decreased Vascular resistance Peripheral vasodilatation

Vasodilation

High cardiac output

Renin angiotensin aldosterone

system

Cardiac failure Sodium and water retention

Edema

Dry Beriberi (paralytic / nervous)

CNS manifestations: muscle weakness gait disturbance paralysis calf muscle tenderness

impairment of sensory, motor and reflex functions ( distal segment of limbs > proximal segment)

Infantile beri-beri:

• Maternal malnutrition

• Age group: 2 – 3 months

• 3 forms Cardiac (acute fulminating) Aphonic Pseudomeningitic

Cerebral Beri beri:

High risk groups: Alcoholism Chronic dialysis

Clinical features: Wernicke’s encephalopathy – ataxia, confusion and

opthalmoplegia.

Korsakoff psychosis – amnesia and confabulation – impairment of conceptual function decreased spontaneity and initiative

Biochemical basis:

• Defective energy metabolism ATP synthesis Altered functions of neurons Degeneration of myelin sheaths

• Defective nerve conductance and neurotransmission

• Synthesis of neurotransmitters

Reason for decreased Neurotransmitters:

Pyruvate Acetyl Co-A

Alpha keto Glutarate

TCA cycle

Glutamate

Acetyl choline B1

B6

GABA

PDH

Choline acetyl transferase

Glutamate decarboxylase

Riboflavin : B2

• Heat stable, light sensitive , luminescent vitamin – UV light

• Vitamin B2 , lactoflavin, Warburg’s yellow enzyme

• Source – whole cereals, legumes (beans), eggs , milk

Co-enzyme forms:

• FMN – Flavin Mono Nucleotide• FAD – Flavin Adenine Dinucletide

• Riboflavin FMN

FAD

Flavokinase

FAD

synthase

Functions:

• Integral component of electron transport chain ATP SYNTHESIS

–NADFMNCoQ• TCA cycle succinate dehydrogenase ATP SYNTHESIS • FATTY ACID OXIDATIONacyl CoA dehydrogenase ATP

SYNTHESIS • As a part of alpha ketoglutarate and isocitrate

dehydrogenase complex ( dihydrolipoate dehydrogenase)

Riboflavin deficiency:

Deficiency manifestations:• Glossitis - inflammation of tongue Magenta red colour(glossitis ), Fissures, Atrophy of lingual papillae

• Cheilosis: fissures in lips

• Angular stomatits: inflammation at corners of mouth

• Conjunctivitis

• Oral-ocular-genital syndrome Angular stomatitis photophobia scrotal dermatitis

Niacin: B3

• Exists in two forms– Nicotinic acid (Niacin)– Nicotinamide (Niacinamide)

• Two coenzyme forms of niacin– NAD+ – NADP+

Function:• Coenzymes are active participants in oxidation-reduction

reactions – Dehydrogenases • Function in at least 200 reaction in cellular metabolic

pathways• NAD+

– Participates in catabolic reactions – Electron and hydrogen ion acceptor

• NADP+– Anabolic reactions – Important in biochemical pathway for fatty-acid synthesis, steroid

and bile acid synthesis.

Tryptophan can be converted to Niacin:

Tryptophan FAD 3-OH-kynurenine kynureninase (-) B6 B6

3-OH-anthranallic acid

Xanthurenic acid Niacin

Deficiency manifestation:• Pellagra– Dementia, Diarrhea, Dermatitis– If not treated can cause death– Develops about 50 to 60 days after a niacin deficient

diet

• Early symptoms– Loss of appetite, weight loss, and weakness

• Mild symptoms– Indigestion, canker sores, vomiting, depression and

fatigue

Pellagra like symptoms can be seen with:

• Niacin deficiency

• Hartnup diseaseLess abspn of Trp

• Carcinoid syndromeexcess Trp going for Serotonin synthesis and less for Niacin synthesis

• Pyridoxine deficiencyKynureninase is not working

• INH (Isoniazid )administration ANTI-TUBERCULOUS DRUG damages liver and increased AST/ALT activity + directly inhibits PLP formation

Uses of Nicotinic acid

Atherosclerosis and Hyperlipidemias:

• By lowering VLDL levels and TG levels mainly .

Pyridoxine: B6

• Three forms :1. Pyridoxine2. Pyridoxal3. Pyridoxamine – antioxidant

Active form of B6 – Pyridoxal phosphate (PLP)

Functions of B6:• Aminoacid metabolism: 1. Transamination2. Deamination3. Decarboxylation4. Transulfuration

• Lipid metabolism : 1. Sphingomyelin synthesis2. Carnitine synthesis

• Carbohydrate metabolism : 1. Glycogenolysis – glycogen phosphorylase 2. Gluconeogenesis –formation of alpha keto acids

Functions:• Heme synthesis

• Catecholamine synthesis

• Niacin synthesis

• Modulation of hormone action – mainly steroids

Transamination reactions :

Aspartate transaminase (AST)

Alanine transaminase (ALT)

Aspartate + α-ketoglutarate

Oxaloacetate + Glutamate

Alanine + α-ketoglutarate

Pyruvate + Glutamate

PLP PLP

• Diagnostic enzymes in various liver diseases:

• Helps in Gluconeogenesis – aminoacid to ketoacids

Decarboxylation reactions:

• Glutamate decarboxylase : Glutamate GABA (inhibitory neurotransmittor)

• Histidine decarboxylase : Histidine Histamine

• DOPA decarboxylase: (catecholamine synthesis) DOPA Dopamine

Transsulfuration :

• Cystathionine β synthase: Homocysteine + serine Cystathionine

• Cystathionase: Cystathionine Homoserine + Cysteine

B6 deficiency Homocysteine

Cardiovascular disease

PLP

PLP

Modulation of hormone action B6 - Remove hormone-receptor complex from DNA

binding

Terminate the action of steroid hormone

B6 deficiency: • Enhances steroid hormone sensitivity• Increases risk for hormone dependent cancers of

breast and uterus

Drugs inactivating PLP:

• Alcohol

• Isoniazid - Anti tubercular

• Carbidopa – used with DOPA in parkinsonism • Penicillamine – chelating agent

• Oral contraceptive pills

Deficiency manifestation:• Neurological manifestations: Peripheral neuritis convulsions

Basis: Formation of catecholamine GABA levels Sphingolipid synthesis Demyelination

• Dermatitis - (pellagra like symptoms)

• Microcytic hypochromic Anemia – decreased formation of Heme

Diagnosis of B6 deficiency:

• Decreased AST and ALT activity

• Methionine load test – Homocysteine and cystathionine in urine.

• Tryptophan load test – Xanthurenic acid

Pantothenic acid: B5

• Contains Pantoic acid (derived from valine) and β-alanine (derived from aspartate)

• Carrier of acyl groups

• Involved in the metabolism of fat, proteins and carbohydrates

• Active form – Coenzyme A (Co-A) Acyl carrier protein.

Functions of Co-A:

1. Cellular metabolism – Co-A derivatives

2. Protein acetylation – Histones and Microtubules

3. Protein acylation – palmitoylation myristoylation of proteins – cell regulation.

4. Detoxification of drugs – acetylation

Cellular metabolism of Co-A:

• Acetyl Co-A• Malonyl Co-A• HMG Co-A• Fatty acyl Co-A• Acetoacetyl Co-A• Succinyl Co-A• Palmitoyl Co-A

TCA cyclefatty acid synthesissteroid metabolismTransportketone body synthesisHeme synthesissphinolipid synthesis

Deficiency manifestations;

• Fatigue, irritability low CoA levels energy production • Neurological symptoms Numbness, muscle cramps acetyl choline formation

• Burning foot syndrome :

• Hypoglycemia : decreased acylation of receptors – increased binding of insulin.

Biotin: B7• Co-enzyme for carboxylation reaction:• Carboxylation require Bicarbonate, ATP and Biotin.

• 5 carboxylation reactions :1. Acetyl Co-A carboxylase isoform –I –cytosol 2. Acetyl Co-A carboxylase isoform - II – outer mit3. Pyruvate carboxylase4. Methyl crotonyl Co-A carboxylase5. Propionyl Co-A carboxylase

Mitochondrial

Biotin deficiency: causes• Consumption of raw egg – Avidin ( binds

biotin)

• Dialysis

Features of biotin deficiency

• Vitamin H – (Haar and Haut) Hair and skin in German

• Biotin deficient facies – unusual fat distribution with a characteristic rash.

Symptoms : 1. Periorificial dermatitis2. Conjunctivitis3. Alopecia4. Neurological – Tingling and numbness ,

depression , lethargy.

Biochemical basis:

• CNS features : Defect in Pyruvate carboxylase lactic acidemia.

• Skin rash and hair loss – due to abnormal fatty acid metabolism mainly of omega -6 – fatty aicds.

• Biotinylation of histones – regulation of transcription and cell proliferation – is affected.

Folate metabolism:• Folic acid is present as various forms of Tetrahydrofolate :

• Acts as a co-enzyme by accepting, transfering, or modyfying one carbon units that are attached to N5 or N10 position of folate.

• Active one carbon donors:1. Formyl THF – purine synthesis2. Methylene THF – pyrimidine synthesis3. Methenyl THF4. Formimino THF

• Predominant form in plasma – methyl THF (reduced) and inactive.

Intermediates

Folate Dihydrofolate

THF

Purine synthesis

Pyrimidine synthesis

Methyl THF (reduced)

Homocysteine

Methionine

B 12Homocysteine methyl transferase

DHFR DHFR Formyl THFMethenyl THFMethylene THF

Folate metabolism:1. DNA synthesis

2. Conversion of Homocysteine to methionine

Methylene tetrahydrofolate reductase

Pyrimidine synthesis:

d-UMP d-TMP

Methylene THF

DHF

Thymidylate synthase

Purine synthesis:

Carbon 2 and 8 of the purine ring is donated by formyl THF

Dihydropteroate + PABA

Dihydrofolate

Dihydropteroate synthtase

Tetrahydrofolate

Dihydrofolate reductase

(-)

(-)

Sulfa drugs

Pyrimethamine

Methotrexate Trimethoprim

protozoa

Eukaryotes/humans

Bacteria

Deficiency of Folate :Causes : • Malabsorption syndromes

• Drugs – Valproic acid – Neural tube defects Sulfasalazine Methotrexate – DHFR inhibitors Alcohol –

• Increased demands – Pregnancy Lactation

Def manifestation:

• Megaloblastic anemia • Homocysteinuria

• Neural tube defects in fetus.

Anemia with MCV > 100• Megaloblastic anemia: form of anemia whose cellular and

nuclear features are characteristic of but not always specific for B12 or folate. It can affect leucocytes and platelets too.

• Macrocytic anemia : increased cell size of RBCs only. The cause can be anything. No changes to leucocytes and platelets.

• Pernicious anemia: reserved for B12 def due to lack of gastric Intrinsic factor. Infact most of the time these persons will not have anemia.

Vitamin B12

• Only animal source – vegetarians ??• Only water soluble vitamin that can be stored

upto some extent• Contains cobalt.

• Synthetic preparation : injectables 1. Hydroxycobalamin2. Cyanocobalamin – easily crystalized and

extracted from bacteria.

Vitamin B12

1. Methyl cobalamin – predominant function in plasma

• Converts homocysteine to methionine with transfer of methyl group from Methyl THF.

• Enzyme – homocysteine methyl transferase/methionine synthase

2. Deoxyadenosylcobalamin – mitochondrial

• Converts methylmalonyl Co-A to succinyl co-A• Enzyme – methyl malonyl Co-A mutase

Absorption of B12:

• Salivary glands – R binder (Haptocorrin-1)

• Gastric parietal cells – Intrinsic factor (IF) HCl – release B12 from food

• Binding of B12 and R-binder in stomach.

• Binds to IF + B12 in duodenum after action of pancreatic enzymes.

• Absorbed in the ileum – cubulin receptors

• Transported by (Haptocorrin -2)

Conversion of methyl malonyl Co-A to succinyl Co-A

Methyl malonyl Co-A mutase

(B12)

Deficiency manifestation:• Megaloblastic anemia

• Methylmalonic aciduria

• Neurological manifestation:

a) Myelopathy – myelin loss, axonal degeneration and Gliosisb) Larger fibres are affected – posterior and lateral columns –

Subacute combined degeneration of spinal chord. c) Loss of vibratory and position sense, ataxia. Intact motor

fibres

Causes :

• Vegan diet

• Pernicious anemia – atrophic gastritis

• Malabsorption syndrome – affecting ileum

• Bacterial overgrowth

• Short bowel syndrome

• Fish tapeworm – diphyllobothrium

Biochemical basis:• Hematological - Folate trap – decreased

methylation of DNA

• Neurological – 1. Abnormal propionate metabolism2. Accumulation of methyl malonyl Co-A –

toxin3. Abnormal fatty acid synthesis and

myelination

Megaloblastic anemia:Vitamin B12 def Folate Def

• Neurological manifestations present

• Methylmalonic aciduria • Pernicious anemia• Develops in years• Vegan diet• Absent• Schilling test

• Absent neurological manifestations

• Absent • Not related• Develops in months • Alcoholism • Neural tube defects in

foetus

Homocysteine

Cystathionine

Cysteine

Methionine

S- Adenosyl Methionine

(SAM)

S- Adenosyl Homocysteine

Methyl THF

THFB12

One carbon donors

PLP

PLP

Cystathionine β synthase

Cystathioninase

Homocysteine methyl transferase

Homocysteine metabolism:

Hyperhomocysteinemia:

• B6 def• Cystathionine beta synthase • Folate def• B12

Increased homocysteine and methionine

Increased homocysteineDecreased methionine

Increased methyl malonic acid in urine

Complications:

• Free sulfur – donates electrons to various molecules to reduce to form water.

• Now the sulfur of homocysteine reacts with sulfur of various proteins to form disulfide links and attach to proteins.

• Clinical features – marfanoid habitus, deep vein thrombosis, atherosclerosis, lens dislocation, joint contractures etc.

Schilling test :

• Stage 1 : oral vitamin B12 plus intramuscular vitamin B12

• Stage 2 : vitamin B12 and intrinsic factor

• Stage 3 : vitamin B12 and antibiotics

• Stage 4 : vitamin B12 and pancreatic enzymes

DHF

THFMethylene THF

Methyl THF

Methionine

Homocyeteine

SAM

SAH

Cystathionine

Cystathionine

B6

B6

B12

B6

MTHFR

DHFR

TSd-UMP

d-TMP

MethenylTHF

FormiminoTHF

THF

FIGLU

GLU

Formyl THF

THF

2 steps in purine synthesis

MS/HMT

Cystathionine beta synthase

Cystathioninase

Integrated metabolism:

SHMT

GlySer