METABOLIC DEFECTS IN AMINO ACID METABOLISM

• Amino acids are the building blocks of proteins and have many functions in the body.

• Hereditary disorders of amino acid metabolism can be the result of defects either in the breakdown of amino acids or in the body's ability to get the amino acids into cells.

• Because these disorders produce symptoms early in life, newborns are routinely screened for several common ones.

• Newborns are screened for:

– Phenylketonuria – Maple syrup urine disease – Homocystinuria – Albinism– Alkaptonuria– Tyrosinemia, and – a number of other inherited disorders, although

screening varies from country to country.

PHENYLKETONURIA

• Phenylketonuria (PKU) is caused by a deficiency of Phenylanine Hydroxylase

• It is the most common clinically encountered inborn error of amino acid metabolism (prevalence is 1 in 15,000)

• Biochemically it is characterized by an accumulation of the amino acid phenylalanine, and sometimes a deficiency of Tyrosine

• Hyper Phenylalaninemia may also be caused by deficiencies in any of the several enzymes required to synthesize BH4, or in dihropteridine (BH2) reductase, which regenerates BH4 from BH2

Synthesis of catecholamines• The catecholamines are synthesized from tyrosine

• Tyrosine is first hydroxylated by tyrosine hydroxylase to form 3,4-dihydroxyphenylalanine (DOPA)

• The tetrahydrobiopterin-requiring enzyme is abundant in the central nervous system, the sympathetic ganglia, and the adrenal medulla, and is the rate-limiting step of the pathway

• DOPA is decarboxylated (decarboxylase) in a reaction requiring pyridoxal phosphate to form dopamine

• which is hydroxylated by the copper-containing dopamine β-hydroxylase to yield norepinephrine.

• Epinephrine is formed from norepinephrine by an N-methylation reaction using S-adenosylmethionine as the methyl donor

• In Parkinson disease --- deficiency of neurotransmitter DOPAMINE

• Such deficiencies indirectly raise phenylanine concentrations, because phenyalanine hydroxylase requires BH4 as a coenzyme

• BH4 is also required for Tyrosine hydroxylase and Tryptophan hydroxylase,

• which catalyze reactions leading to the synthesis of neurotransmitters, such as serotonin and catecholamines.

• Simply restricting dietary phenylanine doesnot reverse the central nervous symptoms effects due to deficiencies in neurotransmitter

• Replacement therapy with BH4 improves the clinical outcome in these variant forms of hyperphenylalaninemia,

• although the response is unpredictable

• Phenylanine is an essential amino acid that cannot be synthesized in the body but is present in food.

• Excess phenylalanine is normally converted to tyrosine, and eliminated from the body.

• Without the enzyme that converts it to tyrosine, phenylalanine accumulates in the blood and is toxic to the brain, causing mental retardation.

• PKU occurs in most ethnic groups.

• If PKU runs in the family and DNA is available from an affected family member,

• amniocentesis or chorionic villus sampling with DNA analysis can be performed to determine whether a fetus has the disorder.

• Most affected newborns are detected during routine screening tests.

• Newborns with PKU rarely have symptoms right away, although sometimes an infant is sleepy or eats poorly.

• If not treated, affected infants progressively develop mental retardation over the first few years of life, which eventually becomes severe.

• Other symptoms include failure to walk or talk, seizures, tremor, microcephaly, nausea and vomiting, an eczema-like rash,

• Lighter skin and hair than their family members, aggressive or self-injurious behavior, hyperactivity, and sometimes psychiatric symptoms.

• Untreated children often give off a "mousy" body and urine odor as a result of a by-product of phenylalanine (Phenyllactate, Phenylacetate and Phenylpyruvate) in their urine and sweat.

• To prevent mental retardation, phenylalanine intake must be restricted (but not eliminated altogether as people need some phenylalanine to live) beginning in the first few weeks of life.

• Because all natural sources of protein contain too much phenylalanine for children with PKU,

• affected children cannot have meat, milk, or other common foods that contain protein.

• Instead, they must eat a variety of phenylalanine-free processed foods, which are specially manufactured.

• Low-protein natural foods, such as fruits, vegetables, and restricted amounts of certain grain cereals, can be eaten.

MAPLE SYRUP URINE DISEASE

• Rare 1 in 185,000

• Autosomal recessive disorder in which there is a partial or complete deficiency in Branched-chain α-keto acid dehyrogenase

• The enzyme complex that decarboxylate Leucine, Isoleucine and Valine

• Children with maple syrup urine disease are unable to metabolize branched amino acids.

• These amino acids and their by-products (α-keto acids) accumulate in the blood,

• causing a toxic effect that interferes with neurologic changes and brain functions, including seizures and mental retardation.

• The disease is characterized by Feeding problems, Vomiting, Dehydration, Severe metabolic acidocis and characteristic maple syrup odor to the urine.

• If untreated the disease leads to mental retardation, physical disabilities and even death

• These by-products also cause body fluids, such as urine and sweat, to smell like maple syrup.

• There are many forms of maple syrup urine disease; symptoms vary in severity.

• In the most severe form, infants develop neurologic abnormalities, including seizures and coma, during the first week of life and can die within days to weeks.

• In the milder forms, children initially appear normal but develop vomiting, staggering, confusion, coma, and the odor of maple syrup particularly during physical stress, such as infection or surgery.

• In some countries, newborns are routinely screened for this disease with a blood test.

• Infants with severe disease are treated with dialysis.

• Some children with mild disease benefit from injections of the vitamin B1 (thiamin).

• After the disease has been brought under control, children must always consume a special artificial diet that is low in branched chain amino acids that are affected by the missing enzyme.

ALBINISM• It is the result of a problem in the biochemical

pathway that converts phenylalanine to melanin.

• It is usually characterized by eye problems; however, people affected by albinism are expected to fulfill a normal lifespan.

• Albinism is a heterogeneous condition inherited through either autosomal recessive or sex-linked recessive genes that affects approximately 1 in 17,000 people.

• It is characterized by a lack of the pigment melanin due to an error in the biochemical pathway that converts phenyalanine to melanin

• Depending on the severity of the break, a person with albinism may not always have a pale complexion, white hair and pink eyes.

• They can sometimes vary from other family members by having a lighter skin tone.

• People with albinism may be affected by a lack of melanin in their hair, skin, and eyes, while others may only have problems with their eyes.

• There are two main types of albinism that are characterized by the areas affected by the abnormality:

• Oculotaneous albinism and Ocular albinism.

• Oculotaneous albinism describes a phenotype that lacks pigment in the skin, hair, and eyes.

• Ocular albinism occurs when the phenotype only lacks pigment from the eyes, the hair and skin appear normal in these individuals.

• Of the two types, oculotaneous albinism is typically more prominent.

• Due to the lack of pigment, people with albinism may also suffer from various eye problems.

• During retina development, the fovea does not develop correctly, and the nerve connections between the retina and the brain become connected abnormally

•

• Affected individuals can suffer from any of the following:

– Nearsightedness – Farsightedness– Astigmatism(distorted images) – Nystagmus(rapid involuntary mov of the eye) – Strabismus(partially closed eyes) – Photosensitivity

• The eye problems may become so severe as to cause the person to be declared legally blind.

• Due to the consistent phenotype of eye problems, the main way to test for albinism is by completing an eye exam.

• Another phenotype of people with albinism is sensitivity to the sun ultra violate rays.

• It is strongly urged that Albinos wear sunscreen at all times because of their high risk of getting sunburn.

• The lack of melanin makes them more susceptible to skin cancer (Melanoma).

• Even though people with albinism may have various medical problems, most fulfill a normal lifespan.

• Some may suffer from various social problems because of their physical appearance.

• In communities of color, one might face discrimination due to people questioning his or her race or paternity.

• Most people with albinism maintain a normal lifestyle.

ALKAPTONURIA

• Alkaptonuria is the first disease to be interpreted as a mendelian recessive trait by Garrod in 1902.

• Alkaptonuria is a rare metabolic disorder resulting from loss of Homogentisate 1,2 dioxygenase activity.

• Affected individuals accumulate large quantities of homogentisic acid, an intermediary product of the catabolism of Tyrosine and Phenylalanine,

• which darkens the urine and deposits in connective tissues causing a debilitating arthritis.

• Alkaptonuria is a rare autosomal recessive inherited disorder caused by defects in the gene encoding an enzyme, homogentisic acid oxidase, involved in the catabolism of Phenylalanine and Tyrosine.

• As a consequence of this gene defect the catabolism of these two amino acids is inhibited and the intermediate homogentisic acid is excreted in the urine.

• If the urine of an individual with alkaptonuria is allowed to stand exposed to the air it will gradually turn dark brown-black as a result of the conversion of homogentisic acid to a melanin-like compound.

• This striking visual sign of alkaptonuria was key to the initial recognition of the disorder which was first described in detail in 1859.

• Garrod, in his seminal 1909 publication (Inborn Errors of Metabolism), described the inherited nature of alkaptonuria.

• In fact, alkaptonuria was not only the first characterized inborn error of metabolism but the first ever disease identified as being inherited. 

• Alkaptonuria is characterized by:

– Homogentisic aciduria – Ochronosis (a bluish-black discoloration of tissues)

and – Arthritis.

• The exact mechanisms by which alkaptonuria results in ochronosis and arthritis are still not fully understood.

• The homogentisic acid oxidase gene (HGO) is found on chromosome 3q21-q23 spanning 60 kb and encompassing 14 exons.

• A number of single nucleotide changes, insertions, deletions, and mutations in introns have been identified in alkaptonuric patients.

• In all, mutations have been found in 11 of the 14 exons of the HGO gene.

Metabolism of sulfur-containing AAs

Methionine cysteine cystineCH2SH

CHNH2

COOH

CH2SH

CHNH2

COOH

CH2

CHNH2

COOH

CH2

CHNH2

COOH

S SCH2

CHNH2

COOH

CH2

CHNH2

COOH

S SS CH3

CH2

CHNH2

COOH

CH2

S CH3

CH2

CHNH2

COOH

CH2

• Methionine condenses with adenosine triphosphate (ATP), forming SAM—a high-energy compound that is unusual in that it contains no phosphate.

• The methyl group attached to the tertiary sulfur in SAM is “activated,” and can be transferred to a variety of acceptor molecules, such as norepinephrine in the synthesis of epinephrine

• After donation of the methyl group, S-adenosylhomocysteine is hydrolyzed to homocysteine and adenosine.

• Homocysteine has two fates. If there is a deficiency of methionine, homocysteine may be remethylated to methionine .

• If methionine stores are adequate, homocysteine may enter the transsulfuration pathway, where it is converted to cysteine.

1. S-adenosyl methionine,SAM

adenosyl transferase

PPi+Pi+

Methionine ATP S-adenosyl methionine,SAM

1. Metabolism of Met

A

A

Methyl transferase

RH RH—CH3Adenosyl/hydroxlation

SAM S—adenosyl homocystein

homocystein

• SAM is the direct donor of methyl in body.

A A

Transmethylation and Met cycle

Trans-Sulfuration PathwayTrans-Sulfuration Pathway

Trans - Sulfuration pathway is analagous to transamination for AA(i) Major degradation pathway for MET in mammals(ii) End Product is CYS(iii) Two RXNs, both use pyridoxal phosphate as a cofactor (as with transamination)

Synthesis of Cys from Met and Ser

HOMOCYSTINURIA

• Children with homocystinuria are unable to metabolize the amino acid Homocysteine due to the defect in the enzyme Cystathionine β–synthase which converts Homocysteine to Cystathionine

• The diseases are inherited as autosomal recessive illness, characterized by:

– High plasma and urinary levels of Homocysteine and methionine and

– Low levels of cysteine.

• Symptoms may be mild or severe, depending on the particular enzyme defect.

• Infants with this disorder are normal at birth.

• The first symptoms, including dislocation of the lens of the eye (Ectopia Lentis), causing severely decreased vision, usually begin after 3 years of age.

• Most children have skeletal abnormalities, including osteoporosis; the child is usually tall and thin with a curved spine, elongated limbs, and long, spiderlike fingers, pre mature arterial disease,

• Psychiatric and behavioral disorders and mental retardation are common.

• Homocystinuria makes the blood more likely to spontaneously clot, resulting in strokes, high blood pressure, and many other serious problems.

• The diagnosis is confirmed by a test measuring enzyme function in liver.

• Some children with homocystinuria improve when given vitamin B6 (pyridoxine) a Coenzyme of Cystathionine β–synthase or vitamin B12 (cobalamin

Hartnup disease-defect transport in intestine& kidney of large neutral aa(Trp)

• Loss of AA in urine• Pellagra like symptoms,diarhoea dermatitis,

dementiaCystinuria-1 in 7,000Defect transport in intestine and kidney of basic

AA.• In kidney cys not reabsorbed forms cystine-

disulfide dimer(insoluble) in urine and cause UTIs and renal stones

• Treatment –Acetazolamide-raise the ph