|Topic:||Lactate Metabolism .|
During anaerobic glycolysis, that period of time when glycolysis is proceeding at a high rate (or in anaerobic organisms), the oxidation of NADH occurs through the reduction of an organic substrate. Erythrocytes and skeletal muscle (under conditions of exertion) derive all of their ATP needs through anaerobic glycolysis. The large quantity of NADH produced is oxidized by reducing pyruvate to lactate. This reaction is carried out by lactate dehydrogenase, (LDH). The lactate produced during anaerobic glycolysis diffuses from the tissues and is transported to highly aerobic tissues such as cardiac muscle and liver. The lactate is then oxidized to pyruvate in these cells by LDH and the pyruvate is further oxidized in the TCA cycle. If the energy level in the liver is high, the carbons of pyruvate will be diverted back to glucose via the gluconeogenesis pathway.
There are two distinct forms of LDH determined by their specificity toward L-lactate and/or D-lactate. These enzymes are encoded for by four different genes in humans identified as LDHA, LDHB, LDHC, and LDHD. Only the LDHD encoded enzyme shows specificity for D-lactate. The LDHA gene encodes the muscle-specific (M) subunit of LDH. The LDHB gene encodes the heart-specific (H) subunit of LDH. As indicated below, different combinations of the M and H subunits generates LDH isoforms in different tissues. The protein encoded by the LDHC gene is found only in the testis. The enzyme encoded by the LDHD gene is a mitochondria-specific enzyme whose expression appears to rise in certain types of cancer (e.g. prostate cancers). The LDHA gene is located on chromosome 11p15.1 and is composed of 9 exons that generate multiple alternatively spliced mRNAs. The LDHB gene is located on chromosome 12p12.1 and is composed of 8 exons that generate two alternatively spliced mRNAs that both encode the same 334 amino acid protein. In addition to the 334 amino acid protein, one of the alternatively spliced LDHB mRNAs encodes a distinct 341 amino acid protein identified as LDHBx. The LDHBx protein results from translational read-through of the normal UGA stop codon with termination occurring at a downstream UAG codon. Analysis of the LDHBx protein demonstrates that several different amino acids (Arg, Cys, Ser, or Trp) can be found at the position of the UGA codon. The LDHBx protein localizes to the peroxisomes. The LDHC gene is located on chromosome 11p15.1 and is composed of 8 exons that generate two alternatively spliced mRNAs that both encode the same 332 amino acid protein. The LDHD gene is located on chromosome 16q23.1 and is composed of 11 exons that generate two alternatively spliced mRNAs encoding two isoforms of this enzyme. Mutations in the LDHA gene are associated with the glycogen storage disease type 11, GSD11.
The majority of the functional LDH in mammalian cells contain various combinations two distinct types of LDH subunits, termed M ( encoded by the LDHA gene) and H (encoded by the LDHB gene). Combinations of these different subunits generate LDH isozymes with different characteristics. The H type subunit predominates in aerobic tissues such as heart muscle (as the H4 tetramer) while the M subunit predominates in anaerobic tissues such as skeletal muscle (as the M4 tetramer). H4 LDH has a low Km for pyruvate and also is inhibited by high levels of pyruvate. The M4 LDH enzyme has a high Km for pyruvate and is not inhibited by pyruvate. This suggests that the H-type LDH is utilized for oxidizing lactate to pyruvate and the M-type is utilized to reduce pyruvate to lactate. The various other isoforms of LDH are described
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