Dr.G.Bhanu Prakash – www.gims-org.

com @ Global institute of Medical sciences – The Medical Biochemistry Tit-Bits

Quick Review of Biochemistry By Dr. Haji Muhammad

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 Degeneration of optic nerve, blindness in early adult
dehydrogenase)
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 Infants: mental retardation, cardiomegaly, death by 2 yrs; juvenile myopathy
(acid maltase) 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-Aheparan sulfate Severe nervous system disorders; mental retardation
Type BN-
acetylglucosaminidase
Type CN-acetyltransferase
Type D N-acetylglucosamine
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)
Type II hyperlipidemia
Type III hyperlipidemia (familial dysbetalipoproteinemia)
Apo C-II, Capillary lipoprotein Accumulation of chylomicrons in plasma; high plasma TAGs and eruptive xanthomas (TAG deposits in skin) and
lipase pancreatitis.
Genetic defect in synthesis, processing or functioning of LDL receptor; elevated LDL levels
Familial hypercholesterolemia
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 Causes: obesity, diabetes mellitus, alcoholism
VLDL secretion
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/ Similar to classic PKU, melatonin and serotonin synthesis also compromised., restrict phenylalanine,
synthase add tyrosine, L-dopa, 5-hydroxytryptophan

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Maternal PKU Mother with either classic or
malignant
Alcaptonuria Homogentisate oxidase
Maple Syrup Urine Disease Branched chain α -ketoacid
dehydrogenase
Propionyl CoA Carboxylase Deficiency Propionyl CoA Carboxylase
Cystathioninuria Cystathionase
Homocystinuria Cystathionine synthetase
Histidinemia Histidase
Albinism Tyrosinase
Tyrosinosis Eumarylacetoacetate hydrolase
Nonketogenic hyperglycinemia Glycine cleavage complex
UREA CYCLE
Type I Hyperammonemia Carbamoylphosphate synthetase I
N-acetylglutamate synthetase deficiency N-acetylglutamate synthetase
Type 2 hyperammonemia Ornithine transcarbmoylase
Classic Citrullinemia Argininosuccunate synthetase
Argininosuccinate Aciduria Argininosuccinate lyase
(argininosuccinase)
Hyperargininemia Arginase
HEME BIOSYNTHESIS/DEGREDATION
Acute Intermittent porphyria Uroporphyrinogen synthase
Congenital erythropoietic porphyria Uroporphyeinogen III synthase
Prophyria Cutanea Tarda Uroporphyrinogen decarboxylase
Hereditary Coproporphyria Coproporphyrinogen oxidase
Varigate Porphyria Protoporphyrin oxidase
Developmental abnormalities, microcephaly, MR, mother didn’t stay within dietary restrictions during
pregnancy
Benign; homogentisate accumulation forms polymers which darkens standing urine. Ochronosis;
darkening of articular cartilage
Elevated levels of α amino acids and their α –keto analogues in plasma and urine; high mortality rate;
neurologic problems
Elevated propionate in blood; accumulation of odd chain FA in liver; developmental problems
Accumulation of cystathionine and metabolites, no clinical symptoms
Accumulation of homocysteine in urine, elevated methionine & metabolites in blood, MR, osteoporosis
Elevated histadine in blood and urine, sometimes MR
Inability to convert tyrosine to melanin
Liver & kidney damage
Severe mental deficiencies & low survival rate past infancy, inc. glycine in blood.
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
Severe/mild hyperammonemia associated wuth deep coma, acidosis, recurrent diarrhea, ataxia, hypoglycemia,
hyperornithinemia; treatment includes administration of carbamoyl glutamate which activates CPS I
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
Episodic hyperammonemia, vomiting, lethargy, ataxia, seizures, coma; treat with arginine to increase
citruline excertion and sodium benzoate to detox ammonia
Episodic symptoms similar to classic citrullinemia, elevated plasma and CSF argininosuccunate;
treat with argentine and sodium benzoate.
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
Autosomal dominant, inc. porphobilinogen & ALA in urine, attacks precipitated by drugs that induce
cytochrome P450 in liver
Inc. uroporphyrinogen I & uroporphyninI
Inc. uroporphyrinogen III which converts to uroporphyrinogen I & coproporphyrinogen I
Inc. coproporphyrinogen III
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 Inc. ALA and protoporphyrin XI, DEC. heme
dehydratase
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/ DEFICIENCY

ACTIVE FORM

B1 Thiamine TPP Beri-beri; Wernicke-Korsakoff

B2 Riboflavin FAD, FMN Dermatitis, cheilosis, glossitis

B3 Niacin NAD, NADP Pellagra; 3 D’s,

B6 Biotin Biotin Adivin; dermatitis, glossitis, anorexia, nausea

B6 Pantothenic acid CoA Not significant

B Folic Acid THF Megaloblastic anemia, neural tube defects, PABA analogues, dihydrofolate inhibitors

B12 Cobalamin 5’deoxyadenosyl cobalamin, Pernicious anemia, CNS symotoms, folate trap
methylcobalamin
B6 Pyridoxine, pyridoxal Pyridoxal PO4 Rare, isoniazid can induce deficiency

C Ascorbic acid Ascorbic acid Scurvey

A Retinol Retinol in vision, retinoic acid in epithelial Blindness, sterility, skin problems
cells
D Cholecalciferol 1,25-diOH D3 Children: rickets, adults: osteomalacia

K Phyllo/menaquinones Same Hypothrombinemia

E Tocopherols α-tocopherol Abnormal cell membranes

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Vitamin Functions Deficiency disease

A Visual pigments in the retina; regulation of gene expression and cell Night blindness, xerophthalmia; keratinization of skin
Retinol, carotene
differentiation ( -carotene is an antioxidant)
D Calciferol Maintenance of calcium balance; enhances intestinal absorption of Ca2+ Rickets = poor mineralization of bone; osteomalacia = bone demineralization
and mobilizes bone mineral; regulation of gene expression and cell
differentiation

E Tocopherols, tocotrienols
K Phylloquinone: menaquinones
B1 Thiamin
Antioxidant, especially in cell membranes; roles in cell signaling Extremely rare—serious neurologic dysfunction
Impaired blood clotting, hemorrhagic disease
Coenzyme in formation of -carboxyglutamate in enzymes of blood
clotting and bone matrix
Peripheral nerve damage (beriberi) or central nervous system lesions (Wernicke-Korsakoff syndrome
Coenzyme in pyruvate and -ketoglutarate dehydrogenases, and
transketolase; regulates Cl– channel in nerve conduction

B2 Riboflavin Coenzyme in oxidation and reduction reactions; prosthetic group of Lesions of corner of mouth, lips, and tongue, seborrheic dermatitis
flavoproteins
Niacin Nicotinic acid, nicotinamide Coenzyme in oxidation and reduction reactions, functional part of NAD Pellagra—photosensitive dermatitis, depressive psychosis
and NADP; role in intracellular calcium regulation and cell signaling
B6 Pyridoxine, pyridoxal, Coenzyme in transamination and decarboxylation of amino acids and Disorders of amino acid metabolism, convulsions
pyridoxamine glycogen phosphorylase; modulation of steroid hormone action
Folic acid Coenzyme in transfer of one-carbon fragments Megaloblastic anemia
B12 Cobalamin Coenzyme in transfer of one-carbon fragments and metabolism of folic Pernicious anemia = megaloblastic anemia with degeneration of the spinal cord
acid
Pantothenic acid Functional part of CoA and acyl carrier protein: fatty acid synthesis and Peripheral nerve damage (nutritional melalgia or "burning foot syndrome")
metabolism
H Biotin Coenzyme in carboxylation reactions in gluconeogenesis and fatty acid Impaired fat and carbohydrate metabolism, dermatitis
synthesis; role in regulation of cell cycle
C Ascorbic acid Coenzyme in hydroxylation of proline and lysine in collagen synthesis; Scurvy—impaired wound healing, loss of dental cement, subcutaneous hemorrhage
antioxidant; enhances absorption of iron

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