BIOCHEMISTRY TRANS 8b - Metabolism of Carbon Skeletons Part 2.pdf

1A BIOCHEMISTRY AMINO ACIDS: METABOLISM OF CARBON SKELETON (Part 2) DR. BRENDO J...

1A BIOCHEMISTRY AMINO ACIDS: METABOLISM OF CARBON SKELETON (Part 2) DR. BRENDO JANDOC M.D. OUTLINE B. Synthesis by amidation I. Role of Folic acid in amino acid metabolism  Glutamine II. Biosynthesis of nonessential amino acid  Contains an amide linkage with ammonia at the ϒ-carboxyl  Synthesis from α-keto acids  Formed from glutamine via glutamine synthetase  Synthesis by amidation  Requires ATP  Proline  Function:  Serine, glycine, cysteine  Protein synthesis  tyrosine  Nontoxic transport form of ammonia III. Metabolic defects in amino acid metabolism  Asparagine  Phenylketonuria  Contains an amide linkage with ammonia at the β-carboxyl  Maple syrup urine disease  Formed from aspartate via asparagine synthetase  Albinism  Requires ATP  Homocystinuria  Equilibrium far in the direction of asparagine synthesis  Alkaptonuria C. Proline  Formed from glutamate ROLE OF FOLIC ACID IN AMINO ACID METABOLISM  Cyclization and reduction reactions  Synthetic pathways D. Serine, Glycine, and Cysteine  Require addition of single carbon groups which exist in  Serine different forms  From 3-phosphoglycerate (intermediate of glycolysis)  Formyl, methenyl, methylene, and methyl  Oxidized to 3-phosphopyruvate  Carried by  Transaminated to 3-phosphoserine  Tetrahydrofolate (THF)  Formed from the hydrolysis of the phosphate ester  S-adenosylmethionine (SAM)  Can be formed from glycine  One-carbon pool  transfer of a hydroxymethyl group by serine  Single carbon units attached to THF or SAM hydroxymethyl transferase  N5,N10-methylene-THF as the one carbon donor A. FOLIC ACID: a carrier of one-carbon unit  Glycine  Tetrahydrofolic acid  Synthesized from glycine  Active form of folic acid  Removal of hydroxymethyl group by serine  Produced by dihydrofolate reductase hydroxymethyl transferase  Two step reaction requiring 2 NADPH  THF as the one carbon acceptor  N5, N10 or both  Cysteine  Carbon containing unit  Two consecutive reactions  Folate deficiency  Cystathione formation  Present as megaloblastic anemia  Serine + homocysteine  cystathione  Decreased availability of purines and TMP needed for DNA  Cystathione hydrolysis synthesis  Cystathione  α-ketobutyrate and cysteine  Homocysteine is derived from methionine (essential amino BIOSYNTHESIS OF NONESSENTIAL AMINO ACIDS acid)  Synthesized from intermediates of metabolism  From the essential amino acids E. Tyrosine  Phenylalanine  Tyrosine  Formed from phenylalanine by phenylalanine hydroxylase  Methionine  Cysteine  Requires molecular oxygen and tetrahydrobiopterin (BH 4) A. Synthesis from α-keto acids  Oxygen becomes hydroxyl group of tyrosine  Alanine, Aspartate, and Glutamate  BH4 can be synthesized from GTP  Transfer of an amino group to  Oxidized to dihydrobiopterin (BH2) the α-keto acids  BH4 regeneration (BH2 to BH4) (TRANSAMINATION – most direct  NADH-requiring dihydropteridine reductase of the biosynthetic pathways)  Formed from essential amino acid  Via aminotransferases  Nonessential in the presence of adequate dietary  Glutamate can also be phenylalanine synthesized by the reverse of the oxidative deamination by METABOLIC DEFECTS IN AMINO ACID METABOLISM glutamate dehydrogenase  Inborn errors of metabolism  Commonly caused by mutant genes Trans FINALS 8b | Abacco, Alderite, Asistin, Balanza, Bayas, Biang 1 of 5  BIOCHEMISTRY AMINO ACIDS: METABOLISM OF CARBON SKELETON (Part 2)  Inherited defects  Hypopigmentation  Total loss of enzyme activity  Fair hair  Partial deficiency of catalytic activity  Light skin color  Untreated  Blue eyes  Mental retardation  Hydroxylation of tyrosine by tyrosinase  Harmful accumulation of metabolites  Formation of Melanin  Newborn screening  Inhibited by the high levels of phenylalanine  Screen for presence of amino acid disorders  Test: Tandem mass spectrometry 2. Neonatal screening and diagnosis of PKU  Sample: Blood obtained from heel stick  Early diagnosis is important  Disease is treatable by dietary means A. PHENYLKETONURIA  Lack of neonatal symptom  Deficiency in phenylalanine hydroxylase  Neonatal screening  Most common clinically encountered inborn error of metabolism  However, infants have normal phenylalanine level  Maternal clearance through the placenta  May persist until newborn is exposed to 24-48 hour protein feeding  SCREENING done after feeding to avoid false negative  Laboratory test for elevated phenylalanine  Quantitative determination of phenylalanine levels  CONFIRMATORY 3. Prenatal diagnosis of PKU  Classic PKU  Accumulation of phenylalanine  100 or more different mutations in the gene that codes for  Can also be caused by dihydropteridine reductase phenylalanine hydroxylase (PAH) deficiency (required to synthesize BH4)  Often doubly heterozygous  INDIRECT – BH4 acts as coenzyme for  PAH has a different mutation in each allele  Phenylalanine hydroxylase  Tyrosine hydroxylase 4. Treatment of PKU  Synthetic amino acid preparations low in phenylalanine  Tryptophan hydroxylase  Phenylalanine maintained close to normal range  Synthesis of neurotransmitters such as  Supplemented with natural food serotonin and catecholamine  Fruit, vegetables, certain cereals  Dietary restriction of phenylalanine  Amount is adjusted according to tolerance  Does not reverse CNS effects  Earlier treatment = preventable neurologic damage  Replacement therapy – improve clinical outcome  Begin 7-10 days of life  BH4 (coenzyme)  Tyrosine becomes essential  L-DOPA  catecholamine  Phenylalanine not converted to tyrosine  5-hydroxytryptophan  serotonin  Overzealous treatment must be avoided  Phenylalanine below normal 1. Characteristics of classic PKU  Lead to poor growth and neurologic symptom  Elevate phenylalanine  Discontinuance of treatment before 8 y/o and adults  Present in tissue, plasma and urine  Poor performance on IQ test  Subsequent elevation of  Treatment must be the LIFELONG phenyllactate, phenylacetate and phenylpyruvate 5. Maternal PKU  Give urine it MUSTY or MOUSY  Maternal PKU syndrome odor  If women with PKU, not in diet, becomes pregnant  CNS symptoms  Present with microcephaly, mental retardation and  Mental retardation congenital heart abnormality  By the age of 1  Phenylalanine is teratogenic  Rarely achieve IQ greater than 50  Dietary control must begin prior to conception  Failure to walk or talk  Maintain throughout pregnancy  Seizure  Hyperactivity  Tremor  Microcephaly  Failure to grow B. MAPLE SYRUP URINE DISEASE Trans FINALS 8b | Abacco, Alderite, Asistin, Balanza, Bayas, Biang 2 of 5  BIOCHEMISTRY AMINO ACIDS: METABOLISM OF CARBON SKELETON (Part 2)  Rare autosomal recessive disorder  Defect in metabolism of homocysteine  Partial or complete deficiency of branched chain α-keto acid  Deficiency in cystathione β-synthase dehydrogenase  Autosomal recessive  Decarboxylation of LIV (leucine, isoleucine, valine)  High plasma and urine level of  Accumulation of LIV homocysteine and methionine  Toxic effect that interferes with brain function  Low levels of cysteine  Characteristics of disease  Homozygous deficiency  Feeding problems  Exhibit ectopia lentis  Vomiting (displacement of the lens of  Dehydration the eye)  Severe metabolic acidosis  Skeletal abnormalities  MAPLE SYRUP odor of urine  Thrombus formation  Osteoporosis 1. Classification  Neurologic deficits  Classic  Treatment  Most common type of MSUD  Oral administration of vitamin B6 (coenzyme)  Leukocytes of cultured skin fibroblasts  Responsive  Little or no branched chain α-keto acid dehydrogenase  Milder and later onset of clinical symptoms  Infants show symptoms within several days of life  Nonresponsive  Untreated  lethal  Restriction of methionine intake  Intermediate form  Supplementation with vitamins B6, B12 and folate.  3-15% enzyme activity  Symptoms are milder E. ALKAPTONURIA  Onset from infancy to adulthood  Deficiency in homogentisic acid oxidase  Thiamine-dependent variant  In the degradative pathway of tyrosine  Thiamine  Accumulation in homogentisic acid  Increases activity of the enzyme  Not life-threatening  But may be severely crippling 2. Screening and Diagnosis  Prenatal diagnosis and neonatal screening 1. Symptoms  Most individuals are compound heterozygotes  Three characteristic symptoms  Homogentisic aciduria 3. Treatment  Oxidation of homogentisic acid  Synthetic formula to a dark pigment in standing  Limited amounts of leucine, isoleucine and valine  Large joint arthritis  Necessary for normal growth and development  Black ochronotic pigmentation of  Nontoxic levels cartilage and collagenous tissue  Important energy source in times of metabolic need  Usually asymptomatic until about 40  Early diagnosis and lifelong treatment y/o  At risk of decompensation in periods of increased protein  Dark staining of the diapers catabolism  May indicate disease in infants C. ALBINISM 2. Treatment  Defect in tyrosine metabolism  Diets low in protein  Deficiency in melanin  Especially phenylalanine and  Partial or full absence of pigment in tyrosine  Skin, hair, and eyes  Help reduce levels of homogentisic  Inherited acid  Autosomal recessive (primary)  Decrease the amount of pigment  Autosomal dominant deposited in body tissues  X-linked  Complete Albinism  Tyrosinase-negative oculocutaneous albinism  Deficiency of copper-requiring tyrosinase  Total absence of pigment  Most severe form  Hypopigmentation, visual defect, and photophobia  Increased risk for skin cancer D. HOMOCYTINURIA Trans FINALS 8b | Abacco, Alderite, Asistin, Balanza, Bayas, Biang 3 of 5  BIOCHEMISTRY AMINO ACIDS: METABOLISM OF CARBON SKELETON (Part 2) SUMMARY: Trans FINALS 8b | Abacco, Alderite, Asistin, Balanza, Bayas, Biang 4 of 5  BIOCHEMISTRY AMINO ACIDS: METABOLISM OF CARBON SKELETON (Part 2) Trans FINALS 8b | Abacco, Alderite, Asistin, Balanza, Bayas, Biang 5 of 5