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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 AND DIE. KAPLAN Step 1 notes. v.Imp  SOURCE OF e 0 -1 for ETC Left untreated death !!. U  T. DNA and RNA synthesis.

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water soluble vitamins

Water soluble vitamins

Dr.S.Chakravarty, MD

slide2

A- ATP

B- BIOTIN

C- CO2

REM - VOMIT

MAIN ATP SYNTHESIS

DECREASEDATP Na+K+ PUMP FAILURE CELLS SWELL AND DIE

KAPLAN Step 1 notes

slide3

v.ImpSOURCE OF e0 -1 for ETC

Left untreated death !!

U T

DNA and RNA synthesis

KAPLAN Step 1 notes

slide4

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 HEMESMALL RBCs IRON NOT USED  IRON DEPOSITED IN PRECURSORS OF RBCSSIDEROBLASTS

slide5

ATP

STOMACH ACIDITY AND VIT C

Fe+3Fe +2

CoA

KAPLAN Step 1 notes

thiamine b1
Thiamine : B1

Source : unpolished rice and whole wheat.(Aleurone layer OF CEREALS )

PARBOILED RICE IS RICH IN THIAMINE

Thiamin status is affected by:

Food processing – washing, polishing etc.

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

Ethanol ingestion / c/c alcoholism (MCC cause of DEFICIENCY )

Reduces thiamin intake

Impairs intestinal absorption

Alters phosphorylation of thiamin

Increases excretion

functions of b1
Functions of B1:

1. Enzyme cofactor: (Thiamine pyrophosphate TPP or TDP)

Oxidative decarboxylation reactions

Pyruvate dehydrogenase

α-ketoglutarate dehydrogenase

α-keto acid dehydrogenase – branched chain amino acid metabolim.

Transketolation reactions

Transketolase – HMP pathway

2 thiamine triphosphate ttp
2. Thiamine Triphosphate (TTP)

Nerve conduction

Phosphorylation of membrane ion channels

Regulates sodium conductance

Neurotransmission

Acetyl choline, Glutamate and GABA synthesis and utilization

Increase neurotransmitter levels in brain.

measurement of thiamine status
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
Deficiency of B1:

Beriberi

Wet beriberi

Dry beriberi

Infantile beriberi

Wernicke-Korsakoff syndrome:

Polyneuritis:

wet beri beri
Wet BeriBeri:

Cardiovascular manifestations

edema

palpitations

breathlessness

fatigue

distended neck veins

cause of death: high ouputcardiac failure

Shoshin beriberi: cyanosis, shock, cardiomegaly

biochemical basis of wet beriberi
Biochemical basis of wet beriberi:

Pyruvate Acetyl CoA

(-)

Lactate

Acidosis

Depression of vasomotor center

Decreased Vascular resistance

Peripheral vasodilatation

slide13

Vasodilation

High cardiac output

Reninangiotensinaldosterone system

Cardiac failure

Sodium and water retention

Edema

dry beriberi paralytic nervous
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
Infantile beri-beri:

Maternal malnutrition

Age group: 2 – 3 months

3 forms

Cardiac (acute fulminating)

Aphonic

Pseudomeningitic

cerebral beri beri
Cerebral Beriberi:

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
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
Reason for decreased Neurotransmitters:

Choline acetyl transferase

PDH

Pyruvate

Acetyl Co-A

Acetyl choline

B1

Alpha ketoGlutarate

Glutamate

Glutamate decarboxylase

B6

TCA cycle

GABA

riboflavin b2
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
Co-enzyme forms:

Flavokinase

FAD synthase

FMN – Flavin Mono Nucleotide

FAD – Flavin Adenine Dinucletide

Riboflavin FMN

FAD

functions
Functions:
  • Integral component of electron transport chain ATP SYNTHESIS
        • NADFMNCoQ
  • TCA cycle succinatedehydrogenase ATP SYNTHESIS
  • FATTY ACID OXIDATIONacylCoAdehydrogenase ATP SYNTHESIS
  • As a part of alpha ketoglutarate and isocitratedehydrogenase complex ( dihydrolipoatedehydrogenase)
deficiency manifestations
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
Niacin: B3
  • Exists in two forms
    • Nicotinic acid (Niacin)
    • Nicotinamide (Niacinamide)
  • Two coenzyme forms of niacin
    • NAD+
    • NADP+
function
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 can be converted to Niacin:

Tryptophan FAD 3-OH-kynurenine

kynureninase

(-) B6 B6

3-OH-anthranallic acid

Xanthurenic acid

Niacin

deficiency manifestation
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
Pellagra like symptoms can be seen with:

Niacin deficiency

HartnupdiseaseLessabspn of Trp

CarcinoidsyndromeexcessTrp going for Serotonin synthesis and less for Niacin synthesis

Pyridoxine deficiencyKynureninase is not working

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

uses of nicotinic acid
Uses of Nicotinic acid

Atherosclerosis and Hyperlipidemias:

By lowering VLDL levels and TG levels mainly .

pyridoxine b6
Pyridoxine: B6

Three forms :

Pyridoxine

Pyridoxal

Pyridoxamine – antioxidant

Active form of B6 – Pyridoxal phosphate (PLP)

functions of b6
Functions of B6:

Aminoacid metabolism:

Transamination

Deamination

Decarboxylation

Transulfuration

Lipid metabolism :

Sphingomyelin synthesis

Carnitine synthesis

Carbohydrate metabolism :

Glycogenolysis – glycogen phosphorylase

Gluconeogenesis –formation of alpha keto acids

functions1
Functions:

Heme synthesis

Catecholamine synthesis

Niacin synthesis

Modulation of hormone action – mainly steroids

transamination reactions
Alaninetransaminase (ALT)Transamination reactions :

Aspartatetransaminase (AST)

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
Decarboxylation reactions:

Glutamate decarboxylase :

Glutamate  GABA (inhibitory neurotransmittor)

Histidinedecarboxylase :

Histidine  Histamine

DOPA decarboxylase: (catecholamine synthesis)

DOPA  Dopamine

transsulfuration
Transsulfuration :

PLP

PLP

Cystathionineβsynthase:

Homocysteine + serine Cystathionine

Cystathionase:

CystathionineHomoserine + Cysteine

B6 deficiency Homocysteine

Cardiovascular disease

modulation of hormone action
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
Drugs inactivating PLP:

Alcohol

Isoniazid - Anti tubercular

Carbidopa – used with DOPA in parkinsonism

Penicillamine – chelating agent

Oral contraceptive pills

deficiency manifestation1
Deficiency manifestation:

Neurological manifestations:

Peripheral neuritis

convulsions

Basis: Formation of catecholamine

GABA levels

Sphingolipid synthesis Demyelination

Dermatitis - (pellagra like symptoms)

Microcytichypochromic Anemia – decreased formation of Heme

diagnosis of b6 deficiency
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
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
Functions of Co-A:

Cellular metabolism – Co-A derivatives

Protein acetylation – Histones and Microtubules

Protein acylation – palmitoylationmyristoylation of proteins – cell regulation.

Detoxification of drugs – acetylation

cellular metabolism of co a
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 cycle

fatty acid synthesis

steroid metabolism

Transport

ketone body synthesis

Heme synthesis

sphinolipid synthesis

deficiency manifestations1
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
Biotin: B7

Mitochondrial

Co-enzyme for carboxylation reaction:

Carboxylation require Bicarbonate, ATP and Biotin.

5 carboxylation reactions :

Acetyl Co-A carboxylaseisoform –I –cytosol

Acetyl Co-A carboxylaseisoform - II – outer mit

Pyruvatecarboxylase

Methyl crotonyl Co-A carboxylase

Propionyl Co-A carboxylase

biotin deficiency causes
Biotin deficiency: causes

Consumption of raw egg – Avidin ( binds biotin)

Dialysis

features of biotin deficiency
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 :

Periorificial dermatitis

Conjunctivitis

Alopecia

Neurological – Tingling and numbness , depression , lethargy.

biochemical basis1
Biochemical basis:

CNS features : Defect in Pyruvatecarboxylase 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
Folate metabolism:

Intermediates

Folic acid is present as various forms of Tetrahydrofolate :

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

Active one carbon donors:

Formyl THF – purine synthesis

Methylene THF – pyrimidine synthesis

Methenyl THF

Formimino THF

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

folate metabolism 1 dna synthesis 2 conversion of homocysteine to methionine
Folate metabolism:1. DNA synthesis2. Conversion of Homocysteine to methionine

Purine synthesis

DHFR

DHFR

Formyl THF

Methenyl THF

Methylene THF

Folate

Dihydrofolate

THF

Pyrimidine synthesis

Methionine

Methylenetetrahydrofolate reductase

Homocysteine methyl transferase

B 12

Homocysteine

Methyl THF

(reduced)

pyrimidine synthesis
Pyrimidine synthesis:

Methylene THF

DHF

d-UMP

d-TMP

Thymidylatesynthase

Purine synthesis:

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

slide51

Dihydropteroate

PABA

+

Dihydropteroatesynthtase

(-)

Sulfa drugs

Dihydrofolate

protozoa

Pyrimethamine

Bacteria

Dihydrofolatereductase

(-)

Trimethoprim

Methotrexate

Tetrahydrofolate

Eukaryotes/humans

deficiency of folate
Deficiency of Folate :

Causes :

Malabsorption syndromes

Drugs –

Valproic acid – Neural tube defects

Sulfasalazine

Methotrexate – DHFR inhibitors

Alcohol –

Increased demands – Pregnancy

Lactation

def manifestation
Def manifestation:

Megaloblastic anemia

Homocysteinuria

Neural tube defects in fetus.

anemia with mcv 100
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 b 12
Vitamin B12

Only animal source – vegetarians ??

Only water soluble vitamin that can be stored upto some extent

Contains cobalt.

Synthetic preparation : injectables

Hydroxycobalamin

Cyanocobalamin – easily crystalized and extracted from bacteria.

vitamin b 121
Vitamin B12

Methyl cobalamin– predominant function in plasma

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

Enzyme – homocysteine methyl transferase/methioninesynthase

2. Deoxyadenosylcobalamin – mitochondrial

Converts methylmalonyl Co-A to succinyl co-A

Enzyme – methyl malonyl Co-A mutase

absorption of b 12
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
Conversion of methyl malonyl Co-A to succinyl Co-A

Methyl malonyl Co-A mutase

Deoxyadenosylcobalamin (B12)

deficiency manifestation2
Deficiency manifestation:

Megaloblastic anemia

Methylmalonicaciduria

Neurological manifestation:

Myelopathy – myelin loss, axonal degeneration and Gliosis

Larger fibres are affected – posterior and lateral columns – Subacute combined degeneration of spinal chord.

Loss of vibratory and position sense, ataxia. Intact motor fibres

causes
Causes :

Vegan diet

Pernicious anemia – atrophic gastritis

Malabsorption syndrome – affecting ileum

Bacterial overgrowth

Short bowel syndrome

Fish tapeworm – diphyllobothrium

biochemical basis2
Biochemical basis:

Hematological - Folate trap – decreased methylation of DNA

Neurological –

Abnormal propionate metabolism

Accumulation of methyl malonyl Co-A –toxin

Abnormal fatty acid synthesis and myelination

megaloblastic anemia
Folate DefMegaloblastic anemia:

Vitamin B12 def

  • Neurological manifestations present
  • Methylmalonicaciduria
  • 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 metabolism
Homocysteine metabolism:

One carbon donors

S- AdenosylMethionine

(SAM)

Methionine

S- AdenosylHomocysteine

THF

B12

Homocysteine methyl transferase

Homocysteine

Methyl THF

PLP

Cystathionineβsynthase

Cystathionine

PLP

Cystathioninase

Cysteine

hyperhomocysteinemia
Hyperhomocysteinemia:

Increased homocysteine and methionine

Increased homocysteine

Decreased methionine

Increased methyl malonic acid in urine

B6 def

Cystathionine beta synthase

Folate def

B12

complications
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 – marfanoidhabitus, deep vein thrombosis, atherosclerosis, lens dislocation, joint contractures etc.

schilling test
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

slide68

THF

Integrated metabolism:

FIGLU

DHF

GLU

d-TMP

DHFR

FormiminoTHF

TS

d-UMP

Ser

Gly

THF

B6

Methylene THF

SHMT

Methenyl

THF

Methionine

MTHFR

MS/HMT

B12

SAM

Methyl THF

Formyl THF

Homocyeteine

SAH

Cystathionine beta synthase

B6

2 steps in purine synthesis

Cystathionine

THF

Cystathioninase

B6

Cystathionine