biochem neuro

8/10/2019 Biochem Neuro

http://slidepdf.com/reader/full/biochem-neuro 1/3

Biochem Neuro:

Tetrahydrobiopterin (BH4) is a cofactor used in the synthesis of tyrosine, dopa, serotonin, and nitric oxide.Initially, tyrosine is converted to DOPA by the enzyme tyrosine hydroxylase, with BH4 present as acofactor. Next, DOPA is decarboxylated to dopamine by the enzyme DOPA carboxylase. In atypical

phenylketonuria (PKU) with tyrosine supplementation, only the catecholamine synthesis reactions

downstream of tyrosine are compromised. The zinc-containing Ö-Aminolevulinate dehydratase and ferrochelatase are enzymes in the heme biosynthetic pathway that are inactivated by lead. Thus, in lead poisoning, Ö-ALA and protoporphyrin IXaccumulate, and the production of heme is decreased, leading to microcytic anemia secondary to a lack ofhemoglobin.

Helicase unwinds DNA at the replication fork and separates dsDNA into ssDNA during the replication process. Initial separation of dsDNA at the origin of replication is facilitated by DnaA protein and strand binding proteins (SSB) proteins.

Peroxisomal diseases are rare inborn errors of metabolism where peroxisomes are either absent ornonfunctional. Very long chain fatty acids or fatty acids with branch points at odd-numbered carbons cannot undergo mitochondrial beta-oxidation; these fatty acids are metabolized by a special form of betaoxidation (very long chain fatty acids) or by alpha oxidation (branched chain fatty acids such as phytanicacid) within peroxisomes. These diseases commonly lead to neurologic defects from improper CNSmyelination.

Arginase is an enzyme of the urea cycle that produces urea and ornithine from arginine. A patient with orotic aciduria (impaired de novo pyrimidine synthesis) will present with hypochromic

megaloblastic anemia, neurologic abnormalities growth, retardation and excretion of orotic acid in theurine. Uridine supplementation improves symptoms by inhibiting carbamoyl phosphate synthetase II.

Propionyl CoA is derived from amino acids (Val, lie Met, and Thr), odd-numbered fatty acids, andcholesterol side chains. Congenital deficiency of propionyl CoA carboxylase, the enzyme responsible forthe conversion of propionyl CoA to methylmalonyl CoA, leads to the development of propionic acidemia.

Branched-chain a-ketoacid dehydrogenase, similar to pyruvate dehydrogenase, requires several coenzymes:TPP, CoA, lipoic acid, NAD, and FAD. Some patients with maple syrup urine disease (MSUD) mayrespond to high-dose thiamine supplementation.

Lesch-Nyhan syndrome is an X-linked recessive disorder caused by a defect in hypoxanthine-guanine phosphoribosyl transferase(HGPRT). This results in failure of the purine salvage pathway. Because theyare not recycled, increased amounts of the purine bases hypoxanthine and guanine are degraded to uricacid. De novo punne synthesis must increase to replace the lost bases

Hydrogen bonds are the principal stabilizing force for the secondary structure of proteins.

Amino groups are released during the metabolism of amino acids. These amino groups are primarilytransferred to α-ketoglutarate to form glutamate the primary carrier of ammonia from the liver. Glutamate

is later excreted by the renal nephron as either a free ion or urea.

Chronic thiamine (B1) deficiency leads to the diminished ability of cerebral cells to utilize glucose. Themechanism is decreased function of the enzymes that use vitamin Bi as a cofactor (pyruvatedehydrogenase, α-ketoglutarate dehydrogenase, and transketolase). Thiamine deficiency can be diagnosed

by measuring erythrocyte transketolase activity.

Vitamin A overuse can result in intracranial hypertension, skin changes, and hepatosplenomegaly.

All three prokaryotic DNA polymerases have proof reading activity and remove mismatched nucleotides

via 3’ to 5’ exonuclease activity. Only DNA polymerase I has 5’ to 3’ exonuc lease activity which is used toexcise and replace RNA primers and damaged DNA sequences.



Maple syrup urine disease (MSUD) is caused by a defect in a-keto acid dehydrogenase, leading to aninability to degrade branched chain amino acids beyond their deaminated a-keto acid state. This illnessclassically results in dystonia and poor feeding as well as the “maple syrup scent” of the patient’s urine

with in the first few days of life. Treatment rests on dietary restriction of branched-chain amino acids. tRNA is the smallest subtype of cellular RNA. Itis responsible for transporting amino acids to the site of

protein synthesis and introducing them into the growing polypeptide chain at the correct locations. The 3-

end of the tRNA molecule is the site of amino acid binding. The opposite side of the molecule contains theanticodon loop which recognizes a specific codon on the mRNA molecule. Deficiency of the enzyme phenylalanine hydroxylase or of its cofactor tetrahydrobiopterin causes

accumulation of phenylalanine in body fluids and the central nervous system (CNS). The homozygousinfant is normal at birth, but mental retardation develops gradually in untreated infants and is frequentlyevident with in six months of life.

Ornithine transport into mitochondria is essential for urea formation, as ornithine is needed to combine withcarbamoyl phosphate within the mitochondria to form citrulline in the second step of the urea cycle. Ureacycle defects cause neurological damage primarily due to the accumulation of ammonia. Protein restrictionwould improve this condition.

Niemann-Pick disease is an autosomal recessive disorder characterized by a deficiency of thesphingomyelinase enzyme and resultant accumulation of sphingomyelin. Patients present in infancy withloss of motor skills, hepatosplenomegaly, hypotonia and a cherry red macular spot. Foamy histiocvtes arethe classic finding on tissue histology. Death occurs before age 3.

N-acetylglutamate is an essential activator of carbamoyl phosphate synthase I and is formed by the enzyme N-acetylglutamate synthetase from the precursors acetyl-CoA and glutamate.

Glucose loading decreases porphyrin synthesis by repressing ALA synthase activity, thus alleviating theabdominal pain and neuropsychiatric manifestations of Acute Intermittent Porphyria (AlP).

In Niemann-Pick disease, deficiency of sphingomyelinase causes abnormal accumulations of the ceramide phospholipid sphingomyelin and neurologic deterioration within the first year of life.

Tyrosine becomes essential in PRU patients because it can no longer be synthesized from phenylalanine.Phenylketonuria (PRU) results from an inability to convert phenylalanine to tyrosine by the phenylalaninehydroxylases system. Although neonatal hyperphenylalaninemia can be caused by deficiencies in any of

the phenylalanine hydroxylases system, most are attributable to abnormalities in the phenylalanine

hydroxylase enzyme.

BH4 is a cofactor used by hydroxylase enzymes in the synthesis of tyrosine, dopa, and serotonin, as well asnitric oxide. Serotonin is synthesized from tryptophan, and the initial step in this reaction is catalyzed by anenzyme that uses 8H4 as a cofactor. Enzyme dihydrobiopterin reductase deficiency causes defective

regeneration of BH4, and is an uncommon cause of phenylketonuria (PKU).

Homocystinuria is caused by cystathionine synthetase deficiency. Affected individuals manifest withskeletal abnormalities resembling those of Marfan syndrome. In addition, they are also at high risk ofdeveloping thromboembolism. About 50% of affected patients respond to high doses of vitamin B6(pyridoxine).

DNA polymerase I has 5’ to 3’ exonuclease activity in addition to its 5’ to 3’ polymerase and 3’ to 5’

exonuclease activities. This 5’ to 3’ exonuclease activity is used to remove the RNA primer (which initiatesDNA polymerization) and to remove damaged DNA.

Ornithine transcarbamoylase deficiency is the most common disorder of the urea cycle, resulting in severeneurological abnormalities due to high blood and tissue ammonia levels. Increased urine orotic acidexcretion is typical.

Methylmalonic acidemia (also known as methylmalonic aciduria) results from a defect in the isomerizationreaction that transforms methylmalonyl CoA to succinyl CoA, prior to succinyl CoA entering the TCACycle.

The nitrogen atoms in the urea molecule are derived from NH3 and aspartate in the urea cycle. Rememberthat carbamoyl phosphate synthetase I (CPS I) is the rate-limiting enzyme in the urea cycle reaction and isactivated by N-acetylglutamate (NAG).



Transamination reactions typically occur between an amino acid and an α-keto acid. The amino group fromthe amino acid is transferred to the a-keto acid, and the a-keto acid in turn becomes an amino acid.Pyridoxal phosphate (vitamin B6) serves as a cofactor in amino acid transamination and in decarboxylationreactions.

biochem neuro

Documents