biochemistry chart dr.g.bhanu prakash

Dr.G.Bhanu Prakash – www.gims-org.com @ Global institute of Medical sciences – The Medical Biochemistry Tit-Bits

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DISORDER ENZYME NOTES

HEMOGLOBINOPATHIES

Sickle Cell anemia (Hemoglobin S disease) Glutamate (HbA) replaced with valine (HbS) on beta chain; anemia, pain, dec. circulation, infections

Hemoglobin C disease Glutamate (HbA) replaced with lysine (HbC) , mild anemia

Hemoglobin SC disease Hbs + HbC, undiagnosed until childbirth / surgery, can be fatal

Methemoglobinemia NADH cytochrome b5 reductase Diminished oxygen-carring capacity of ferric Hb (metHb) headache, lightheadedness, dyspenea and chocolate

cyanosis

THALASSEMIAS

Α-thalassemia: Silent Carrier 1 defective No symptoms

Mild Symptoms 2 defective 2 alpha chains missing

Hb B 4 defective Accumulation of γ4 tetramers in newborns, HYDROPS FATALIS

HbH 3 defective Accumulation of β4 tetramers in newborns, severe anemia

Β-thalassemia: major Deletion of both betas Both β chains defective, fatal HEINZ bodies, inability of HbF HbA, manifests around 8 mos old.

Minor Deletion of 1 beta chain Only 1 β chain defective, not fatal

COLLAGEN DISEASES

Scurvy Proly/lysyl hydroxylase Vit C def. no hydroxylation

Ehlers-Danlos Lysyl hydroxylase Stretchy skin, loose joints, aortic aneurysm, ruptured colon,

Osteogenesis Imperfecta Collagen Type 1 defect Brittle bones in babies, blue sclera, multiple fractures, slowed healing

Type 1: heterozygous, postnatal, can survive

Type 2: homozygous, perinatal, death in utero

Emphysema α1- anti-trypsin deficiency Inherited defect in alpha 1 anti-trypsin resulting in emphysema

Alport’s Affect glomerular basement membrane, hearing loss, ocular defects

Goodpasture’s Antibodies destroy basement membrane of pulmonary and glomerular capillaries

Menke’s Lysyl oxidase/Cu2+

Deficient cross linking secondary to functional copper deficiency; depigmented

(steely) hair, arterial tortuosity and rupture, cerebral degeneration, anemia, osteoporosis.

ETC INHIBITORS

Electron transport blockers Complex1 NADH dehydrogenase Amobarbital, rotenone

Complex III cytochrome reductase Antimycin A

Complex IV cytochrome oxidase CO,CN

Complex V (ATP synthase) Oligomycin

TCA CYCLE

Fluoroacetate Aconitase Inhibited

Malonate Succinate dehydrogenase Inhibited

Arsenite Α-ketogluconate dehydrogenase Inhibited

HEREDITARY MITOCHONDRIAL DISEASES

Leber’s hereditary optic neuropathy Complex 1 (NADH

dehydrogenase)

Degeneration of optic nerve, blindness in early adult

Kearns-Sayre Ragged red fibers, heart block, retinal pigmentation


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MELAS Mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like episodes

MERRF Myoclonus epilepsy with ragged red fibers; ataxia, sensorineural deafness

GLUCOSE & PYRUVATE METABOLISM

Pyruvate dehydrogenase deficiency Pyruvate dehydrogenase Lactic acidosis, neurologic defects (Wernicke-Korsakoff)

Pyruvate DH complex deficiency Pyruvate DH complex Pyuvate to lactate, neonatal death, infancy death, episodic ataxia after meal

Arsenic poisoning G3PDH Lost NADH, pyruvate accumulates

Pyruvate kinase deficiency Pyruvate kinase Most common enzyme deficiency in glycolytic pathway; hemolytic anemia, jaundice

GALACTOSE METABOLISM

Classical galactosemia GALT Cirrhosis, mental retardation, cataracts, galactosuria

Galactokinase deficiency Galactokinase Cataracts, galactosemia, galactosuria

UDP galactose 4-epimerase deficiency Benign: affects RBCs and WBCs Malignant: similar to GALT def

FRUCTOSE METABOLISM

Hereditary fructose intolerance Aldolase B Toxic liver damage, renal disease, hypophosphatemia, gout

Essential fructosuria Fructokinase Benign condition, fructosuria

HMP PATHWAY/NADPH RELATED DISORDERS

Hemolytic Anemia G6PD X linked, hemolytic anemia often induced by infections, oxidant drugs & fava beans; inadequate NADPH

production results in reduction in antioxidant activity of glutathione in mature RBC’s

Class I: chronic nonspherocytin anemia, most severe

Class II: Mediterranean, normal stability, scarce activity in RBCs

Class III: A-, oldest RBCs removed

Amyotrophic Lateral Sclerosis Superoxide dismutase Degenerated motor neurons in CNS

Chronic granulomatosis NADPH oxidase Persistant chronic pyogenic infections; deficiency of enzyme located in leukocyte membrane

GLYCOGEN STORAGE DISEASES

Type 0 Glycogen synthase Hypoglycemia, death, hyperketonia

VON Gierke’s (Type 1) Glucose 6-phosphate Hepatosplenomegaly, severe fasting hypoglycemia

Pompe’s (Type II) α-1-4 glucosidase

(acid maltase)

Infants: mental retardation, cardiomegaly, death by 2 yrs; juvenile myopathy

Adult: gradual skeletal myopathy

Cori’s (Type III) α-1-6 glucosidase Mild hypoglycemia, hepatomegaly

Andersen’s (Type IV) Glucosyl-4-6-transferase Hepatosplenomegaly, liver failure, death by 2 yrs

McArdle’s (Type V) Muscle glycogen phosphorylase Muscle cramping, fatigue, no increase in lactic acid after exercise

Hers’ (Type VI) Liver glycogen phosphorylase Mild hypoglycemia

Mucopolysaccharidoses

Hurler’s α-L-iduronidase Corneal clouding, MR, coarse facial features, early death

Hunter’s Iduronate sulfatase X-linked, physical deformity, MR


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Sanfilippo’s Types A-D Type-Aheparan sulfate

Type BN-

acetylglucosaminidase Type CN-acetyltransferase

Type D N-acetylglucosamine

Severe nervous system disorders; mental retardation

Scheie’s α-L-iduronidase Like Hurler’s but normal life span

Sly’s β-glucronidase Hepatosplenomegaly, physical deformity

Synthesis of glycoproteins

I-cell disease Lysosomal hydrolytic enzymes Deficiency in ability to phosphorylated mannose residuesof potential lysosomal enzymes;

results in incorrect targeting of glycoproteins; death by 8 yrs; elevated N-linked glycoproteins in urine.

Metabolism of Dietary Lipids

Congenital A-beta-lipoproteinemia Apo B-48 Accum of chylomicrons in enterocytes

Type 1 hyperlipidemia (familial hyperchylomicronemia) Apo C-II, Capillary lipoprotein

lipase

Accumulation of chylomicrons in plasma; high plasma TAGs and eruptive xanthomas (TAG deposits in skin) and

pancreatitis.

Type II hyperlipidemia Genetic defect in synthesis, processing or functioning of LDL receptor; elevated LDL levels

Familial hypercholesterolemia

Type III hyperlipidemia (familial dysbetalipoproteinemia) Apolipoprotein E Accumulation of chylomicron remnants in plasma

Type IV hyperlipidemia Inc. VLDL due to obesity, alcohol, diabeties

Type V hyperlilidemia Inc. chylomicrons, TAGs, VLDL, pancreatitis

Wolman disease Cannot hydrolyze lysosomal cholesteryl esters

Familial LCAT deficiency Complete absence of LCAT, low HDL

Fish Eye Disease Partial LCAT absense

Zellweger syndrome Defective peroxisomal biogenesis, accumulated VLCFAs in blood

X-linked Leukodystrophy Defective peroxisomal activation of VLCFAs, destroyed myelin

Mobilization of Stored Fats & [FA]

Carnitine deficiency inability to use long chain FA as fuel, causes: congenital, liver disease

CAT-1 def Liver cannot synthesize glucose during fast, hypoglycemia, coma, death

CAT-2 def Cardiomyopathy, muscle weakness following exercise

Medium chain Fattyacyl CoA dehydrogenase deficiency Medium chain fatty acyl CoA Decreased FA oxidation, severe hypoglycemia; cause of 10% SIDS cases, Reyes syndrome; treat with

high carb diet

Paroxysomal Nocturnal Hemoglobinuria GPI synthase In hematopoietic cells

Refsum disease Fatty acid alpha-hydroxylase AR, increased phytanic acid, neurologic symptoms


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Vit B12 def Methylmalonic academia and aciduria, metabolic acidosis

Phospholipid metabolism

Niemann-Pick Type A Sphingomyelinase Cherry red macula, hepatosplenomegaly, severe mental retardation, death in early childhood

Type B Chronic lung damage, death in early adulthood

Type C Sphingomyelinase Cannot transport unesterified cholesterol out of lysosomes

SPHINGOLIPIDOSES

Tay-Sachs β-hexoaminidase A Cherry-red macula inc. GM2, blindness, MR, early death

Gaucher’s β-glucosidase Sphingolipidosis, inc. glucocerebrosides, hepatosplenomegaly, MR, frequently fatal

Metachromatic leukodystrophy Arylsuldatase A MR, demyelination, fatal in 1st decade

Krabbe’s β-galactosidase Inc. galactocerebrosides, MR, almost total absence of myelin, fatal

GM1 gangliosidosis β-galactosidase GM1 accumulation, MR, skeletal deformities, death

Sandhoff’s disease Β-hexosaminidase A & B Inc. globosides; same symptoms as Tay-Sachs with rapid progression.

Fabry’s α-galactosidase Inc. globosides; X linked, kidney & heart failure, redish purple skin rash

Farber’s Ceraminidase Inc. ceramide, painful and progressively deformed joints; granulomas, fatal early in life

Cholesterol & steroid metabolism CAH Congenital Adrenal Hyperplasia

Smith-Lemli-Opitz Syndrome 7-hydrocholesterol-7-reductase AR, double bond migration (Lanosterol to Cholesterol)

Fatty Liver Imbalanced TG synthesis and VLDL secretion

Causes: obesity, diabetes mellitus, alcoholism

Cholelithiasis Cholesterol gallstones Malabsorption, obstructed biliary tract, hepatic dysfunction; treat: laparoscopic cholecystectomy

3-β-hydroxysteroid dehydrogenase def 3-β-hydroxysteroid dehydrogenase Inc. pregnenolone, No glucocorticoids, mineralocorticoids, androgens, or estrogen; early death

17-α -hydroxylase deficiency 17-α -hydroxylase Sex hormones & cortisol not produced inc. production of aldosterone gives HTN, phenotypically female

but unable to mature

21-α -hydroxylase deficiency 21-α -hydroxylase Most common CAH; ACTH levels inc. gives inc. sex hormones & masculinization

11-β-hydroxylase deficiency 11-β -hydroxylase Dec. cortisol & aldesterone; masculization

AMINO ACID METABOLISM

Classic PKU Phenylalanine hydroxylase MR, dec. melanin synthesis; fair skin, mousy odor, congenital pyloric stenosis, screen after 1st exposure

to phenylalanine in breat milk, restrict phenylalanine intake, increase tyrosine

Malignant PKU Dihydrobiopterin reductase/

synthase

Similar to classic PKU, melatonin and serotonin synthesis also compromised., restrict phenylalanine,

add tyrosine, L-dopa, 5-hydroxytryptophan


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Maternal PKU Mother with either classic or

malignant

Developmental abnormalities, microcephaly, MR, mother didn’t stay within dietary restrictions during

pregnancy

Alcaptonuria Homogentisate oxidase Benign; homogentisate accumulation forms polymers which darkens standing urine. Ochronosis;

darkening of articular cartilage

Maple Syrup Urine Disease Branched chain α -ketoacid

dehydrogenase

Elevated levels of α amino acids and their α –keto analogues in plasma and urine; high mortality rate;

neurologic problems

Propionyl CoA Carboxylase Deficiency Propionyl CoA Carboxylase Elevated propionate in blood; accumulation of odd chain FA in liver; developmental problems

Cystathioninuria Cystathionase Accumulation of cystathionine and metabolites, no clinical symptoms

Homocystinuria Cystathionine synthetase Accumulation of homocysteine in urine, elevated methionine & metabolites in blood, MR, osteoporosis

Histidinemia Histidase Elevated histadine in blood and urine, sometimes MR

Albinism Tyrosinase Inability to convert tyrosine to melanin

Tyrosinosis Eumarylacetoacetate hydrolase Liver & kidney damage

Nonketogenic hyperglycinemia Glycine cleavage complex Severe mental deficiencies & low survival rate past infancy, inc. glycine in blood.

UREA CYCLE

Type I Hyperammonemia Carbamoylphosphate synthetase I Within 24-48 hrs after birth infant becomes increasingly lethargic, needs stimulation to feed, vomiting,

hypothermia, & hyperventilation; without appropriate intervention death occurs; treat with arginine which

activates N-acetylglutamate synthetase

N-acetylglutamate synthetase deficiency N-acetylglutamate synthetase Severe/mild hyperammonemia associated wuth deep coma, acidosis, recurrent diarrhea, ataxia, hypoglycemia,

hyperornithinemia; treatment includes administration of carbamoyl glutamate which activates CPS I

Type 2 hyperammonemia Ornithine transcarbmoylase Most commonly occurring UCD, only X linked, increased ammonia and aa in serum, increased serum orotic acid due to mitochondrial carbamoylphosphate entering cytosoland incorporating in pyrimidine

nucleotides leading to excess productin and excess catabolic products; treat with high carb, low protein diet,

and sodium phenylacetate/benzoate for ammonia detox

Classic Citrullinemia Argininosuccunate synthetase Episodic hyperammonemia, vomiting, lethargy, ataxia, seizures, coma; treat with arginine to increase

citruline excertion and sodium benzoate to detox ammonia

Argininosuccinate Aciduria Argininosuccinate lyase

(argininosuccinase)

Episodic symptoms similar to classic citrullinemia, elevated plasma and CSF argininosuccunate;

treat with argentine and sodium benzoate.

Hyperargininemia Arginase Rare UCD progressive spastic quadriplegia and MR high ammonia & arginine in CSF & serum, high arginine,

lysine, and ornithine in urine; treat with low protein diet including essential AA but no arginine

HEME BIOSYNTHESIS/DEGREDATION

Acute Intermittent porphyria Uroporphyrinogen synthase Autosomal dominant, inc. porphobilinogen & ALA in urine, attacks precipitated by drugs that induce

cytochrome P450 in liver

Congenital erythropoietic porphyria Uroporphyeinogen III synthase Inc. uroporphyrinogen I & uroporphyninI

Prophyria Cutanea Tarda Uroporphyrinogen decarboxylase Inc. uroporphyrinogen III which converts to uroporphyrinogen I & coproporphyrinogen I

Hereditary Coproporphyria Coproporphyrinogen oxidase Inc. coproporphyrinogen III

Varigate Porphyria Protoporphyrin oxidase Accumulation of protoporphyrinogen IX


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Erythropoietic Protoporphyria Ferrochelatase Accumulation of protoporphyrin IX

Sideroblastic Anemia ALA synthase X-linked

Crigler-Najjar syndrome Bilirubin glucuronyl transferase In newborns: newborn jaundice, treat with blue light

Lead poisoning ferrochelatase/ ALA

dehydratase

Inc. ALA and protoporphyrin XI, DEC. heme

CONGENITAL ADRENAL HYPERPLASIA

3-β-hydroxysteroid DH def. No glucocorticoids, mineralocorticoids, androgens/estrogens, hyponatremia, feminine genitalia,

early death

17-α-hydroxylase def. No sex hormones, cortisol, inc. mineralocorticoids, hypernatremia, HTN, feminine genitalia,

early death

21-α-hydroxylase def. Greater than 90% CAH, no mineralo/glucocorticoids, inc. androgens, masculinization

11-β-hydroxylase def. Dec. cortisol, aldesterone, and corticosterone, inc. deoxycorticosterone; fluid retention, HTN,

masculinization

LETTER NAME COENZYME/

ACTIVE FORM

DEFICIENCY REACTIONS TYPE

B1 Thiamine TPP Beri-beri; Wernicke-Korsakoff Transketolase, PDC and α-KG Dehydrogenase

Oxidative, decaeboxyl ation, transfer of α-ketols

B2 Riboflavin FAD, FMN Dermatitis, cheilosis, glossitis Succinate DH Redox

B3 Niacin NAD, NADP Pellagra; 3 D’s, Redox

B6 Biotin Biotin Adivin; dermatitis, glossitis, anorexia, nausea Acetyl carboxylase,propionyl

carboxulase, pyruvate carboxylase

Carboxylation

B6 Pantothenic acid CoA Not significant Citrate & FA synthase Acyl carrier

B Folic Acid THF Megaloblastic anemia, neural tube defects, PABA analogues, dihydrofolate inhibitors Purine & thymine síntesis, Met, Ser,

Gly, Cys

1 C metabolism

B12 Cobalamin 5’deoxyadenosyl cobalamin,

methylcobalamin

Pernicious anemia, CNS symotoms, folate trap Synth of Met & isomerization of

methylmalonyl CoA succinyl CoA

B6 Pyridoxine, pyridoxal Pyridoxal PO4 Rare, isoniazid can induce deficiency AST,ALT Transamination,

deamination

C Ascorbic acid Ascorbic acid Scurvey Hydroxylation of praline in collagen Antioxidant, hydrox of

Praline & lysine

A Retinol Retinol in vision, retinoic acid in epithelial

cells

Blindness, sterility, skin problems Visual cycle

D Cholecalciferol 1,25-diOH D3 Children: rickets, adults: osteomalacia Calcium levels in plasma

K Phyllo/menaquinones Same Hypothrombinemia Formation of g-carboxyglutamate Carboxylation of

certain Glu residues

E Tocopherols α-tocopherol Abnormal cell membranes Anti-oxidant


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Vitamin Functions Deficiency disease

A

Retinol, carotene

Visual pigments in the retina; regulation of gene expression and cell

differentiation ( -carotene is an antioxidant)

Night blindness, xerophthalmia; keratinization of skin

D Calciferol Maintenance of calcium balance; enhances intestinal absorption of Ca2+

and mobilizes bone mineral; regulation of gene expression and cell

differentiation

Rickets = poor mineralization of bone; osteomalacia = bone demineralization

E Tocopherols, tocotrienols Antioxidant, especially in cell membranes; roles in cell signaling Extremely rare—serious neurologic dysfunction

K Phylloquinone: menaquinones

Coenzyme in formation of -carboxyglutamate in enzymes of blood

clotting and bone matrix

Impaired blood clotting, hemorrhagic disease

B1

Thiamin

Coenzyme in pyruvate and -ketoglutarate dehydrogenases, and

transketolase; regulates Cl– channel in nerve conduction

Peripheral nerve damage (beriberi) or central nervous system lesions (Wernicke-Korsakoff syndrome)

B2

Riboflavin Coenzyme in oxidation and reduction reactions; prosthetic group of

flavoproteins

Lesions of corner of mouth, lips, and tongue, seborrheic dermatitis

Niacin Nicotinic acid, nicotinamide Coenzyme in oxidation and reduction reactions, functional part of NAD

and NADP; role in intracellular calcium regulation and cell signaling

Pellagra—photosensitive dermatitis, depressive psychosis

B6

Pyridoxine, pyridoxal,

pyridoxamine

Coenzyme in transamination and decarboxylation of amino acids and

glycogen phosphorylase; modulation of steroid hormone action

Disorders of amino acid metabolism, convulsions

Folic acid Coenzyme in transfer of one-carbon fragments Megaloblastic anemia

B12

Cobalamin Coenzyme in transfer of one-carbon fragments and metabolism of folic

acid

Pernicious anemia = megaloblastic anemia with degeneration of the spinal cord

Pantothenic acid Functional part of CoA and acyl carrier protein: fatty acid synthesis and

metabolism

Peripheral nerve damage (nutritional melalgia or "burning foot syndrome")

H Biotin Coenzyme in carboxylation reactions in gluconeogenesis and fatty acid

synthesis; role in regulation of cell cycle

Impaired fat and carbohydrate metabolism, dermatitis

C Ascorbic acid Coenzyme in hydroxylation of proline and lysine in collagen synthesis;

antioxidant; enhances absorption of iron

Scurvy—impaired wound healing, loss of dental cement, subcutaneous hemorrhage

biochemistry chart dr.g.bhanu prakash

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